rs17097458

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004086.3(COCH):c.1477+9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 1,613,692 control chromosomes in the GnomAD database, including 3,469 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 302 hom., cov: 33)

Exomes 𝑓: 0.059 ( 3167 hom. )

Consequence

COCH
NM_004086.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.328

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 (BayesDel_noAF=-0.77).

BP6

Variant 14-30886321-C-A is Benign according to our data. Variant chr14-30886321-C-A is described in ClinVar as [Benign]. Clinvar id is 226528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-30886321-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COCH	NM_004086.3 linkuse as main transcript	c.1477+9C>A		intron_variant		ENST00000396618.9
LOC100506071	NR_038356.1 linkuse as main transcript	n.544G>T		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COCH	ENST00000396618.9 linkuse as main transcript	c.1477+9C>A		intron_variant		1	NM_004086.3	P1	O43405-1
	ENST00000555108.1 linkuse as main transcript	n.544G>T		non_coding_transcript_exon_variant	3/5	1

Frequencies

GnomAD3 genomes

AF:

0.0533

AC:

8112

AN:

152128

Hom.:

301

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0248

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0711

Gnomad ASJ

AF:

0.0276

Gnomad EAS

AF:

0.182

Gnomad SAS

AF:

0.0840

Gnomad FIN

AF:

0.0710

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0538

Gnomad OTH

AF:

0.0516

GnomAD3 exomes

AF:

0.0667

AC:

16628

AN:

249448

Hom.:

753

AF XY:

0.0675

AC XY:

9134

AN XY:

135312

show subpopulations

Gnomad AFR exome

AF:

0.0247

Gnomad AMR exome

AF:

0.0655

Gnomad ASJ exome

AF:

0.0300

Gnomad EAS exome

AF:

0.176

Gnomad SAS exome

AF:

0.0898

Gnomad FIN exome

AF:

0.0647

Gnomad NFE exome

AF:

0.0529

Gnomad OTH exome

AF:

0.0563

GnomAD4 exome

AF:

0.0592

AC:

86463

AN:

1461446

Hom.:

3167

Cov.:

AF XY:

0.0601

AC XY:

43695

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.0223

Gnomad4 AMR exome

AF:

0.0666

Gnomad4 ASJ exome

AF:

0.0291

Gnomad4 EAS exome

AF:

0.171

Gnomad4 SAS exome

AF:

0.0907

Gnomad4 FIN exome

AF:

0.0655

Gnomad4 NFE exome

AF:

0.0539

Gnomad4 OTH exome

AF:

0.0603

GnomAD4 genome

AF:

0.0533

AC:

8122

AN:

152246

Hom.:

302

Cov.:

AF XY:

0.0557

AC XY:

4147

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0249

Gnomad4 AMR

AF:

0.0710

Gnomad4 ASJ

AF:

0.0276

Gnomad4 EAS

AF:

0.183

Gnomad4 SAS

AF:

0.0840

Gnomad4 FIN

AF:

0.0710

Gnomad4 NFE

AF:

0.0537

Gnomad4 OTH

AF:

0.0553

Alfa

AF:

0.0517

Hom.:

182

Bravo

AF:

0.0510

Asia WGS

AF:

0.138

AC:

479

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	1477+9C>A in Intron 11 of COCH: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce and has been identified in 5.3% (369/7014) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS; dbSNP rs17097458). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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+	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Autosomal dominant nonsyndromic hearing loss 9

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

Cadd

Benign

9.6

Dann

Benign

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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