rs121908931

Positions:

• chr14-30878926-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_Supporting BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.355G>A variant in COCH is a missense variant predicted to cause substitution of alanine by threonine at amino acid 119. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.394, which is neither above nor below the thresholds predicting a damaging or benign impact on COCH function. Functional studies show no differences between wild-type and p.A119T variant cochlin localization and secretion (BS3_Supporting). While this is not supporting evidence for pathogenicity, other mechanisms of pathogenicity cannot be ruled out. Due to conflicting evidence, this variant is classified as a variant of unknown significance for autosomal dominant nonsyndromic genetic deafness based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, BS3_P (Hearing Loss VCEP specifications version 2; 6/15/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA253893/MONDO:0019497/005

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: COCH NM_004086.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 0.954

Genes affected

COCH (HGNC:2180): (cochlin) The protein encoded by this gene is highly conserved in human, mouse, and chicken, showing 94% and 79% amino acid identity of human to mouse and chicken sequences, respectively. Hybridization to this gene was detected in spindle-shaped cells located along nerve fibers between the auditory ganglion and sensory epithelium. These cells accompany neurites at the habenula perforata, the opening through which neurites extend to innervate hair cells. This and the pattern of expression of this gene in chicken inner ear paralleled the histologic findings of acidophilic deposits, consistent with mucopolysaccharide ground substance, in temporal bones from DFNA9 (autosomal dominant nonsyndromic sensorineural deafness 9) patients. Mutations that cause DFNA9 have been reported in this gene. Alternative splicing results in multiple transcript variants encoding the same protein. Additional splice variants encoding distinct isoforms have been described but their biological validities have not been demonstrated. [provided by RefSeq, Oct 2008]

ENSG00000258525 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COCH	NM_004086.3	c.355G>A	p.Ala119Thr	missense_variant	5/12	ENST00000396618.9	NP_004077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COCH	ENST00000396618.9	c.355G>A	p.Ala119Thr	missense_variant	5/12	1	NM_004086.3	ENSP00000379862.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 9 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2003

- -

Nonsyndromic genetic hearing loss Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jun 15, 2022

The c.355G>A variant in COCH is a missense variant predicted to cause substitution of alanine by threonine at amino acid 119. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.394, which is neither above nor below the thresholds predicting a damaging or benign impact on COCH function. Functional studies show no differences between wild-type and p.A119T variant cochlin localization and secretion (BS3_Supporting). While this is not supporting evidence for pathogenicity, other mechanisms of pathogenicity cannot be ruled out. Due to conflicting evidence, this variant is classified as a variant of unknown significance for autosomal dominant nonsyndromic genetic deafness based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, BS3_P (Hearing Loss VCEP specifications version 2; 6/15/2022). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	.;T;T;.;.;.;T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.69	T;.;.;T;T;T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.55	.;N;N;.;N;.;.;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.63	.;N;.;.;N;N;N;.
REVEL	Uncertain	0.39
Sift	Benign	0.13	.;T;.;.;T;T;D;.
Sift4G	Benign	0.11	.;T;.;.;T;D;T;.
Polyphen		0.0	.;B;B;.;.;.;.;B
Vest4		0.35, 0.66, 0.20
MutPred		0.73		.;Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);.;.;Gain of loop (P = 0.0851);
MVP		0.85
MPC		0.28
ClinPred		0.60	D
GERP RS		3.9
Varity_R		0.064
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908931; hg19: chr14-31348132;