14-30886321-C-A

Variant names:

• chr14-30886321-C-A
• rs17097458
• ENST00000555108.1:n.544G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000555108.1(ENSG00000258525):​n.544G>T variant causes a non coding transcript exon 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: ENSG00000258525 ENST00000555108.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.328
• Publications: 10 publications found

Genes affected

ENSG00000258525 (HGNC:58454):

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 226528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
COCH	NM_004086.3	c.1477+9C>A		intron_variant	Intron 11 of 11	ENST00000396618.9	NP_004077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COCH	ENST00000396618.9	c.1477+9C>A		intron_variant	Intron 11 of 11	1	NM_004086.3	ENSP00000379862.3

Frequencies

GnomAD3 genomes AF: 0.0533 AC: 8112 AN: 152128 Hom.: 301 Cov.: 33

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

GnomAD2 exomes AF: 0.0667 AC: 16628 AN: 249448 AF XY: 0.0675

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 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.: 34 AF XY: 0.0601 AC XY: 43695 AN XY: 727048

African (AFR) AF: 0.0223 AC: 747 AN: 33474

American (AMR) AF: 0.0666 AC: 2976 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 760 AN: 26130

East Asian (EAS) AF: 0.171 AC: 6777 AN: 39700

South Asian (SAS) AF: 0.0907 AC: 7817 AN: 86176

European-Finnish (FIN) AF: 0.0655 AC: 3496 AN: 53370

Middle Eastern (MID) AF: 0.0552 AC: 318 AN: 5766

European-Non Finnish (NFE) AF: 0.0539 AC: 59932 AN: 1111764

Other (OTH) AF: 0.0603 AC: 3640 AN: 60380

GnomAD4 genome AF: 0.0533 AC: 8122 AN: 152246 Hom.: 302 Cov.: 33 AF XY: 0.0557 AC XY: 4147 AN XY: 74428

African (AFR) AF: 0.0249 AC: 1033 AN: 41532

American (AMR) AF: 0.0710 AC: 1086 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 96 AN: 3472

East Asian (EAS) AF: 0.183 AC: 946 AN: 5168

South Asian (SAS) AF: 0.0840 AC: 405 AN: 4820

European-Finnish (FIN) AF: 0.0710 AC: 753 AN: 10608

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0537 AC: 3655 AN: 68024

Other (OTH) AF: 0.0553 AC: 117 AN: 2114

Alfa AF: 0.0544 Hom.: 517

Bravo AF: 0.0510

Asia WGS AF: 0.138 AC: 479 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 03, 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. -

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

- -

Autosomal dominant nonsyndromic hearing loss 9 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.6
DANN	Benign	0.64
PhyloP100		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17097458; hg19: chr14-31355527;