rs1045644

Positions:

• chr14-30885890-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.97

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]

(HGNC:):

ACMG classification

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	UniProt
COCH	NM_004086.3	c.1055C>G	p.Thr352Ser	missense_variant	11/12	ENST00000396618.9
LOC100506071	NR_038356.1	n.975G>C		non_coding_transcript_exon_variant	3/5

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.514 AC: 78143 AN: 152032 Hom.: 22143 Cov.: 33

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

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.: 49 AF XY: 0.596 AC XY: 433266 AN XY: 727036

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.: 33 AF XY: 0.513 AC XY: 38117 AN XY: 74374

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:10

Revision: criteria provided, multiple submitters, no conflicts

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	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). -
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	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. -

Autosomal dominant nonsyndromic hearing loss 9 Benign:4

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	Genome-Nilou Lab	Jul 22, 2021	- -
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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hearing loss, autosomal recessive 110 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
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	N
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	T
MutationAssessor	Benign	-1.0	.;N;N;.;N;.;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.40	T
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	T
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

Other links and lift over

dbSNP: rs1045644; hg19: chr14-31355096; COSMIC: COSV53549551; COSMIC: COSV53549551;