rs121908931

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. BS3_SupportingPM2_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

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:1

Conservation

PhyloP100: 0.954

Publications

14 publications found

Variant links:

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]

COCH Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant nonsyndromic hearing loss 9
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive 110
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COCH links:

ENSG00000258525 (HGNC:58454):

ENSG00000258525 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
COCH	NM_004086.3 link	c.355G>A	p.Ala119Thr	missense_variant	Exon 5 of 12	ENST00000396618.9	NP_004077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COCH	ENST00000396618.9 link	c.355G>A	p.Ala119Thr	missense_variant	Exon 5 of 12	1	NM_004086.3	ENSP00000379862.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.000176

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111986

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 9

Pathogenic:1

Oct 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nonsyndromic genetic hearing loss

Uncertain:1

Jun 15, 2022

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

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

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

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

LIST_S2

Benign

0.69

T;.;.;T;T;T;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.29

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.55

.;N;N;.;N;.;.;N

PhyloP100

0.95

PrimateAI

Benign

0.32

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

GERP RS

3.9

Varity_R

0.064

gMVP

0.41

Mutation Taster

=3/97

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over