Autosomal dominant nonsyndromic hearing loss 70

Summary

Autosomal dominant nonsyndromic hearing loss 70 (MONDO:0014853) is a disease caused by MCM2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: MCM2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nonsyndromic hearing loss 70
Mondo ID	MONDO:0014853
OMIM	616968
DOID	DOID:0110592
UMLS	C4310775
MedGen	934742
GARD	0018145
Is cancer (heuristic)	no

Also known as: autosomal dominant deafness 70 · autosomal dominant nonsyndromic deafness 70 · autosomal dominant nonsyndromic deafness caused by mutation in MCM2 · autosomal dominant nonsyndromic deafness type 70 · autosomal dominant nonsyndromic hearing loss 70 · deafness, autosomal dominant 70 · deafness, autosomal dominant type 70 · DFNA70 · MCM2 autosomal dominant nonsyndromic deafness

Data availability: 15 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant nonsyndromic hearing loss › autosomal dominant nonsyndromic hearing loss 70

Related subtypes (75): autosomal dominant nonsyndromic hearing loss 1, autosomal dominant nonsyndromic hearing loss 2A, autosomal dominant nonsyndromic hearing loss 4A, autosomal dominant nonsyndromic hearing loss 6, autosomal dominant nonsyndromic hearing loss 5, autosomal dominant nonsyndromic hearing loss 10, autosomal dominant nonsyndromic hearing loss 11, autosomal dominant nonsyndromic hearing loss 9, autosomal dominant nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 12, autosomal dominant nonsyndromic hearing loss 3A, autosomal dominant nonsyndromic hearing loss 13, autosomal dominant nonsyndromic hearing loss 15, autosomal dominant nonsyndromic hearing loss 17, autosomal dominant nonsyndromic hearing loss 16, autosomal dominant nonsyndromic hearing loss 20, autosomal dominant nonsyndromic hearing loss 23, autosomal dominant nonsyndromic hearing loss 25, autosomal dominant nonsyndromic hearing loss 18, autosomal dominant nonsyndromic hearing loss 24, autosomal dominant nonsyndromic hearing loss 22, autosomal dominant nonsyndromic hearing loss 30, autosomal dominant nonsyndromic hearing loss 36, autosomal dominant nonsyndromic hearing loss 21, autosomal dominant nonsyndromic hearing loss 44, autosomal dominant nonsyndromic hearing loss 48, autosomal dominant nonsyndromic hearing loss 41, autosomal dominant nonsyndromic hearing loss 49, autosomal dominant nonsyndromic hearing loss 43, autosomal dominant nonsyndromic hearing loss 28, autosomal dominant nonsyndromic hearing loss 31, autosomal dominant nonsyndromic hearing loss 47, autosomal dominant auditory neuropathy 1, autosomal dominant nonsyndromic hearing loss 53, autosomal dominant nonsyndromic hearing loss 27, autosomal dominant nonsyndromic hearing loss 59, autosomal dominant nonsyndromic hearing loss 3B, autosomal dominant nonsyndromic hearing loss 2B, autosomal dominant nonsyndromic hearing loss 50, autosomal dominant nonsyndromic hearing loss 51, autosomal dominant nonsyndromic hearing loss 64, autosomal dominant nonsyndromic hearing loss 33, autosomal dominant nonsyndromic hearing loss 4B, autosomal dominant nonsyndromic hearing loss 56, autosomal dominant nonsyndromic hearing loss 54, autosomal dominant nonsyndromic hearing loss 58, autosomal dominant nonsyndromic hearing loss 65, autosomal dominant nonsyndromic hearing loss 67, autosomal dominant nonsyndromic hearing loss 40, autosomal dominant nonsyndromic hearing loss 69, autosomal dominant nonsyndromic hearing loss 68, autosomal dominant nonsyndromic hearing loss 66, hearing loss, autosomal dominant 74, hearing loss, autosomal dominant 77, hearing loss, autosomal dominant 81, hearing loss, autosomal dominant 82, hearing loss, autosomal dominant 83, hearing loss, autosomal dominant 84, hearing loss, autosomal dominant 80, hearing loss, autosomal dominant 37, hearing loss, autosomal dominant 75, hearing loss, autosomal dominant 76, hearing loss, autosomal dominant 71, hearing loss, autosomal dominant 72, hearing loss, autosomal dominant 73, hearing loss, autosomal dominant 34, with or without inflammation, hearing loss, autosomal dominant 78, hearing loss, autosomal dominant 79, hearing loss, autosomal dominant 85, hearing loss, autosomal dominant 86, hearing loss, autosomal dominant 87, hearing loss, autosomal dominant 88, hearing loss, autosomal dominant 89, hearing loss, autosomal dominant 90, autosomal dominant nonsyndromic hearing loss 91

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

15 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 2 benign, 1 likely benign, 1 no classifications from unflagged records, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1032222	NM_004526.4(MCM2):c.1231G>A (p.Glu411Lys)	MCM2	Uncertain significance	criteria provided, single submitter
1032223	NM_004526.4(MCM2):c.1447C>T (p.Pro483Ser)	MCM2	Uncertain significance	criteria provided, single submitter
1032224	NM_004526.4(MCM2):c.277G>A (p.Glu93Lys)	MCM2	Uncertain significance	criteria provided, single submitter
1338855	NM_004526.4(MCM2):c.388C>T (p.Arg130Cys)	MCM2	Uncertain significance	criteria provided, single submitter
1431208	NM_004526.4(MCM2):c.2444G>A (p.Arg815His)	MCM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1485868	NM_004526.4(MCM2):c.1510C>A (p.Pro504Thr)	MCM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2297766	NM_004526.4(MCM2):c.850C>T (p.Arg284Cys)	MCM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
235129	NM_004526.4(MCM2):c.130C>T (p.Arg44Cys)	MCM2	no classifications from unflagged records	no classifications from unflagged records
3124299	NM_004526.4(MCM2):c.1684C>T (p.Arg562Trp)	MCM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891640	NM_004526.4(MCM2):c.758C>T (p.Ala253Val)	MCM2	Uncertain significance	criteria provided, single submitter
522730	NM_004526.4(MCM2):c.1624C>T (p.Arg542Ter)	MCM2	Uncertain significance	criteria provided, single submitter
1316816	NM_004526.4(MCM2):c.449A>G (p.Lys150Arg)	MCM2	Likely benign	criteria provided, multiple submitters, no conflicts
2506305	NM_004526.4(MCM2):c.53G>C (p.Arg18Pro)	MCM2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
508098	NM_004526.4(MCM2):c.504C>T (p.Ile168=)	MCM2	Benign	criteria provided, multiple submitters, no conflicts
508099	NM_004526.4(MCM2):c.2013+10A>G	MCM2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MCM2	Strong	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 70	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MCM2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MCM2	HGNC:6944	ENSG00000073111	P49736	DNA replication licensing factor MCM2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MCM2	DNA replication licensing factor MCM2	Acts as a component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for ‘once per cell cycle’ DNA replication initiation and elongation in eukaryotic cells.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MCM2	Other/Unknown	no		MCM_dom, MCM2, NA-bd_OB-fold

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
secondary oocyte	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MCM2	234	broad	marker	oocyte, secondary oocyte, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MCM2	4,472

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCM2	P49736	39

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	1631.4×	0.008	MCM2
DNA strand elongation	1	1142.0×	0.008	MCM2
Unwinding of DNA	1	878.5×	0.008	MCM2
Activation of the pre-replicative complex	1	326.3×	0.008	MCM2
DNA Replication Pre-Initiation	1	317.2×	0.008	MCM2
Activation of ATR in response to replication stress	1	300.5×	0.008	MCM2
Switching of origins to a post-replicative state	1	300.5×	0.008	MCM2
Synthesis of DNA	1	300.5×	0.008	MCM2
DNA Replication	1	237.9×	0.008	MCM2
G1/S Transition	1	233.1×	0.008	MCM2
Mitotic G1 phase and G1/S transition	1	184.2×	0.008	MCM2
S Phase	1	181.3×	0.008	MCM2
MITF-M-dependent gene expression	1	181.3×	0.008	MCM2
Orc1 removal from chromatin	1	178.4×	0.008	MCM2
Assembly of the pre-replicative complex	1	139.3×	0.010	MCM2
G2/M Checkpoints	1	134.3×	0.010	MCM2
MITF-M-regulated melanocyte development	1	114.2×	0.011	MCM2
Cell Cycle Checkpoints	1	88.5×	0.013	MCM2
Cell Cycle, Mitotic	1	48.2×	0.023	MCM2
Cell Cycle	1	36.0×	0.029	MCM2
Developmental Biology	1	14.5×	0.069	MCM2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitotic DNA replication initiation	1	2808.7×	0.003	MCM2
double-strand break repair via break-induced replication	1	1296.3×	0.003	MCM2
regulation of DNA-templated DNA replication initiation	1	1053.2×	0.003	MCM2
cellular response to interleukin-4	1	648.1×	0.003	MCM2
DNA replication initiation	1	624.1×	0.003	MCM2
cochlea development	1	468.1×	0.003	MCM2
DNA replication	1	165.2×	0.008	MCM2
nucleosome assembly	1	140.4×	0.008	MCM2
apoptotic process	1	28.7×	0.035	MCM2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MCM2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MCM2	22	Binding:22

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MCM2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MCM2	22	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.