# NM_017780.4(CHD7):c.2124T>C (p.Ser708=)

https://sugi.bio/variant/chd7-p-ser708

## Summary

**CHD7 p.Ser708= (c.2124T>C)** is classified **Benign/Likely benign** in CHD7 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-03). Common (popmax 5.54%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs79302359 · 13 submitters · 3 linked conditions · common (popmax 5.54%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CHD7 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 13 submitters, and is linked to Inborn genetic diseases.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHD7](https://sugi.bio/atlas/gene/CHD7/) |
| Protein change (HGVS p.) | p.Ser708= |
| Coding change (HGVS c.) | c.2124T>C |
| MANE Select transcript | [NM_017780](https://www.ncbi.nlm.nih.gov/nuccore/NM_017780) |
| dbSNP | [rs79302359](https://www.ncbi.nlm.nih.gov/snp/rs79302359/) |
| Variant type | single nucleotide variant |
| Location | chr8:60795013-60795013 (GRCh38) |
| ClinVar | [VCV95777](https://www.ncbi.nlm.nih.gov/clinvar/variation/95777/) |

**All HGVS expressions:** `LRG_176:g.121234T>C`, `LRG_176t1:c.2124T>C`, `NC_000008.10:g.61707572T>C`, `NC_000008.11:g.60795013T>C`, `NG_007009.1:g.121234T>C`, `NM_001316690.1:c.1716+13963T>C`, `NM_017780.4:c.2124T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 5.54%, afr) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 4.18, GERP 0.737, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 11.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for CHD7 (2,800 scored positions, the nearest 7 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **5.54%** (afr) · FAF95 5.4% · FAF99 5.35% · 4,158/74,998 in the highest group · 12,419/1,613,616 alleles overall — common (popmax 5.54%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 5.54% | 18 |
| South Asian | 4.95% | 20 |
| Middle Eastern | 4.05% | 25 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.53% | 65 |
| Remaining individuals (not grpmax-eligible) | 1.11% | 90 |
| Admixed American | 0.522% | 192 |
| European (non-Finnish) | 0.173% | 578 |
| East Asian | 0.0111% | 8,972 |
| Finnish (not grpmax-eligible) | 0.00781% | 12,798 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CHD7** population constraint: LOEUF 0.109, pLI 1, missense-Z 3.9606; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **CHARGE syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **708** lies in the 'disordered' region.

**3 experimental structure(s)** (PDB): [2CKC](https://www.rcsb.org/structure/2CKC), [2V0E](https://www.rcsb.org/structure/2V0E), [2V0F](https://www.rcsb.org/structure/2V0F).

## What this gene does {#gene-function}

*Describes the biological roles of CHD7 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

CHD7 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CHD6, CHD7, CHD8, CHD9 subfamily](https://reactome.org/content/detail/R-HSA-9943962) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** skeletal system development, in utero embryonic development, heart morphogenesis, central nervous system development, cranial nerve development, T cell differentiation.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-03.

**Submitter consensus:** conflicting (12 Benign, 1 Likely benign).

**Submission history:** 13 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-09-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |
| Genetic Services Laboratory, University of Chicago | Benign | criteria provided, single submitter | clinical testing | 2013-02-08 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2018-08-08 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2014-10-28 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2019-05-13 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2016-05-06 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [CHARGE syndrome](https://sugi.bio/atlas/disease/charge-syndrome/), [hypogonadotropic hypogonadism 5 with or without anosmia](https://sugi.bio/atlas/disease/hypogonadotropic-hypogonadism-5-with-or-without-anosmia/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not specified, CHARGE syndrome, Hypogonadotropic hypogonadism 5 with or without anosmia, not provided, AllHighlyPenetrant, CHARGE ASSOCIATION--COLOBOMA, HEART ANOMALY, CHOANAL ATRESIA, RETARDATION, GENITAL AND EAR ANOMALIES, Hittner Hirsch Kreh syndrome, Coloboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies, CHARGE association.

## Similar variants {#similar}

Related CHD7 variant pages (same residue, condition, or type): [CHD7 p.Ser708Asn](/variant/chd7-p-ser708asn), [CHD7 c.2097-2A>G](/variant/chd7-c-2097-minus-2a-g), [CHD7 c.2238+1G>A](/variant/chd7-c-2238-plus-1g-a), [CHD7 c.2377-1G>A](/variant/chd7-c-2377-minus-1g-a), [CHD7 c.2613+1G>A](/variant/chd7-c-2613-plus-1g-a), [CHD7 c.2836-1G>A](/variant/chd7-c-2836-minus-1g-a), [CHD7 c.2836-2A>T](/variant/chd7-c-2836-minus-2a-t), [CHD7 c.2957+2T>C](/variant/chd7-c-2957-plus-2t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 95777). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*