rs1045644

Positions:

chr14-30885890-C-G

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 226525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-30885890-C-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
COCH	NM_004086.3 linkuse as main transcript	c.1055C>G	p.Thr352Ser	missense_variant	11/12	ENST00000396618.9	NP_004077.1
LOC100506071	NR_038356.1 linkuse as main transcript	n.975G>C		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COCH	ENST00000396618.9 linkuse as main transcript	c.1055C>G	p.Thr352Ser	missense_variant	11/12	1	NM_004086.3	ENSP00000379862	P1	O43405-1
	ENST00000555108.1 linkuse as main transcript	n.975G>C		non_coding_transcript_exon_variant	3/5	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

GnomAD3 exomes

AF:

0.558

AC:

140099

AN:

251088

Hom.:

41625

AF XY:

0.553

AC XY:

74989

AN XY:

135692

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 SAS exome

AF:

0.358

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

Gnomad4 AFR exome

AF:

0.254

Gnomad4 AMR exome

AF:

0.645

Gnomad4 ASJ exome

AF:

0.595

Gnomad4 EAS exome

AF:

0.334

Gnomad4 SAS exome

AF:

0.362

Gnomad4 FIN exome

AF:

0.645

Gnomad4 NFE exome

AF:

0.640

Gnomad4 OTH exome

AF:

0.564

GnomAD4 genome

AF:

0.514

AC:

78167

AN:

152150

Hom.:

22153

Cov.:

AF XY:

0.513

AC XY:

38117

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.273

Gnomad4 AMR

AF:

0.608

Gnomad4 ASJ

AF:

0.599

Gnomad4 EAS

AF:

0.348

Gnomad4 SAS

AF:

0.350

Gnomad4 FIN

AF:

0.662

Gnomad4 NFE

AF:

0.633

Gnomad4 OTH

AF:

0.540

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	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). -

Autosomal dominant nonsyndromic hearing loss 9

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Hearing loss, autosomal recessive 110

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

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

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

MutationTaster

Benign

1.0

P;P;P;P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over