rs1045644

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004086.3(COCH):c.1055C>G(p.Thr352Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 1,613,614 control chromosomes in the GnomAD database, including 295,272 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 22153 hom., cov: 33)

Exomes 𝑓: 0.60 ( 273119 hom. )

Consequence

COCH
NM_004086.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.97

Publications

55 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.766174E-5).

BP6

Variant 14-30885890-C-G is Benign according to our data. Variant chr14-30885890-C-G is described in ClinVar as Benign. ClinVar VariationId is 226525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COCH	NM_004086.3 link	c.1055C>G	p.Thr352Ser	missense_variant	Exon 11 of 12	ENST00000396618.9	NP_004077.1	O43405-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COCH	ENST00000396618.9 link	c.1055C>G	p.Thr352Ser	missense_variant	Exon 11 of 12	1	NM_004086.3	ENSP00000379862.3		O43405-1

Frequencies

GnomAD3 genomes

AF:

0.514

AC:

78143

AN:

152032

Hom.:

22143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.273

Gnomad AMI

AF:

0.718

Gnomad AMR

AF:

0.607

Gnomad ASJ

AF:

0.599

Gnomad EAS

AF:

0.349

Gnomad SAS

AF:

0.350

Gnomad FIN

AF:

0.662

Gnomad MID

AF:

0.541

Gnomad NFE

AF:

0.633

Gnomad OTH

AF:

0.545

GnomAD2 exomes

AF:

0.558

AC:

140099

AN:

251088

AF XY:

0.553

show subpopulations

Gnomad AFR exome

AF:

0.261

Gnomad AMR exome

AF:

0.649

Gnomad ASJ exome

AF:

0.598

Gnomad EAS exome

AF:

0.360

Gnomad FIN exome

AF:

0.652

Gnomad NFE exome

AF:

0.635

Gnomad OTH exome

AF:

0.595

GnomAD4 exome

AF:

0.603

AC:

880660

AN:

1461464

Hom.:

273119

Cov.:

AF XY:

0.596

AC XY:

433266

AN XY:

727036

show subpopulations

African (AFR)

AF:

0.254

AC:

8510

AN:

33476

American (AMR)

AF:

0.645

AC:

28845

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.595

AC:

15548

AN:

26130

East Asian (EAS)

AF:

0.334

AC:

13257

AN:

39692

South Asian (SAS)

AF:

0.362

AC:

31192

AN:

86246

European-Finnish (FIN)

AF:

0.645

AC:

34474

AN:

53410

Middle Eastern (MID)

AF:

0.550

AC:

3171

AN:

5768

European-Non Finnish (NFE)

AF:

0.640

AC:

711589

AN:

1111650

Other (OTH)

AF:

0.564

AC:

34074

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

20258

40516

60775

81033

101291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18592

37184

55776

74368

92960

<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

AF:

0.514

AC:

78167

AN:

152150

Hom.:

22153

Cov.:

AF XY:

0.513

AC XY:

38117

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.273

AC:

11312

AN:

41502

American (AMR)

AF:

0.608

AC:

9298

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.599

AC:

2080

AN:

3472

East Asian (EAS)

AF:

0.348

AC:

1803

AN:

5180

South Asian (SAS)

AF:

0.350

AC:

1688

AN:

4818

European-Finnish (FIN)

AF:

0.662

AC:

6998

AN:

10570

Middle Eastern (MID)

AF:

0.541

AC:

159

AN:

294

European-Non Finnish (NFE)

AF:

0.633

AC:

43035

AN:

68000

Other (OTH)

AF:

0.540

AC:

1139

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1776

3552

5328

7104

8880

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

668

1336

2004

2672

3340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.605

Hom.:

21510

Bravo

AF:

0.505

TwinsUK

AF:

0.625

AC:

2318

ALSPAC

AF:

0.649

AC:

2502

ESP6500AA

AF:

0.282

AC:

1244

ESP6500EA

AF:

0.630

AC:

5415

ExAC

AF:

0.549

AC:

66605

Asia WGS

AF:

0.337

AC:

1174

AN:

3478

EpiCase

AF:

0.624

EpiControl

AF:

0.625

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thr352Ser in Exon 11 of COCH: This variant is not expected to have clinical sign ificance because it has been identified in 37.1% (2602/7020) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs1045644). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 9

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hearing loss, autosomal recessive 110

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.033

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

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.44

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

MetaRNN

Benign

0.000018

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

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.0

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

PhyloP100

2.0

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.98

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

REVEL

Benign

0.23

Sift

Benign

0.034

D;T;.;.;T;T;.

Sift4G

Benign

1.0

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

Polyphen

0.0

.;B;B;.;.;.;B

Vest4

0.048, 0.018, 0.045

MutPred

0.13

.;Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);

MPC

0.19

ClinPred

0.0024

GERP RS

4.2

Varity_R

0.053

gMVP

0.16

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over