# NM_014171.6(CRIPT):c.138-5del

https://sugi.bio/variant/cript-c-138-minus-5del

## Summary

**CRIPT c.138-5del** is classified **Benign** in CRIPT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-14). Low-frequency (popmax 1.38%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs60552651 · 3 submitters · low-frequency (popmax 1.38%, afr)

## For patients & families {#patients}

This is a change in the CRIPT gene that is classified as benign — not considered disease-causing, submitted by 3 submitters.

*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 | [CRIPT](https://sugi.bio/atlas/gene/CRIPT/) |
| Coding change (HGVS c.) | c.138-5del |
| MANE Select transcript | [NM_014171](https://www.ncbi.nlm.nih.gov/nuccore/NM_014171) |
| dbSNP | [rs60552651](https://www.ncbi.nlm.nih.gov/snp/rs60552651/) |
| Variant type | Deletion |
| Location | chr2:46623757-46623757 (GRCh38) |
| ClinVar | [VCV775712](https://www.ncbi.nlm.nih.gov/clinvar/variation/775712/) |

**All HGVS expressions:** `NC_000002.11:g.46850898del`, `NC_000002.12:g.46623759del`, `NG_034144.1:g.11588del`, `NM_014171.5:c.138-5del`, `NM_014171.6:c.138-5del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 1.396, GERP -3.55, phastCons 0.022 — weakly conserved position
- CADD: **PHRED 0.031**. 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.*
- Splice region: **acceptor splice region (-5, within the last 20 intronic nt)** — inside the zone ClinGen GN167 excludes from BP7, so this variant must not be called benign merely for being synonymous or intronic.
- Non-coding constraint (Gnocchi): **Z -1.71**, o/e 1.12 (1 kb window 46,623,000–46,624,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **1.38%** (afr) · FAF95 1.31% · FAF99 1.28% · 1,008/73,048 in the highest group · 1,106/1,556,584 alleles overall — low-frequency (popmax 1.38%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.38% | 72 |
| Remaining individuals (not grpmax-eligible) | 0.078% | 1,282 |
| Admixed American | 0.0759% | 1,317 |
| South Asian | 0.00229% | 43,661 |
| European (non-Finnish) | 0.000528% | 189,353 |

*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}

**CRIPT** population constraint: LOEUF 1.852, pLI 0.18985, missense-Z -0.57206; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 78.77, 36% of residues very-high.

**1 experimental structure(s)** (PDB): [7DVQ](https://www.rcsb.org/structure/7DVQ).

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

*Describes the biological roles of CRIPT (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.*

**How this variant is thought to act:** CRIPT's established molecular role includes PDZ domain binding.


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

**Molecular function:** PDZ domain binding, scaffold protein binding.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-14.

**Submitter consensus:** unanimous (3/3 Benign).

**Submission history:** 3 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Benign | criteria provided, single submitter | clinical testing | 2018-07-16 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2024-08-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-14 |

**Reported phenotype names (ClinVar):** not provided, not specified, CRIPT-related disorder, CRIPT-related condition, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related CRIPT variant pages (same residue, condition, or type): [CRIPT c.-422_17-582del](/variant/cript-c-minus-422-17-minus-582del), [CRIPT c.138-11_138-8del](/variant/cript-c-138-minus-11-138-minus-8del), [CRIPT c.242-15_242-14del](/variant/cript-c-242-minus-15-242-minus-14del), [CRIPT c.83-10_83-5del](/variant/cript-c-83-minus-10-83-minus-5del), [CRIPT p.Phe47fs](/variant/cript-p-phe47fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 775712). 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.*