rs139503327

Variant names:

• chr14-30886183-A-G
• rs139503327
• NM_004086.3:c.1348A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004086.3(COCH):​c.1348A>G​(p.Ile450Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000748 in 1,610,614 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (3 hom.)
• Consequence: COCH NM_004086.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 7.52
• Publications: 4 publications found

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

ENSG00000258525 (HGNC:58454):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05638054).
• BP6: Variant 14-30886183-A-G is Benign according to our data. Variant chr14-30886183-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228523.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000853 (130/152322) while in subpopulation AMR AF = 0.00177 (27/15294). AF 95% confidence interval is 0.00125. There are 0 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004086.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COCH	NM_004086.3	MANE Select	c.1348A>G	p.Ile450Val	missense	Exon 11 of 12	NP_004077.1
	COCH	NM_001347720.2		c.1543A>G	p.Ile515Val	missense	Exon 10 of 11	NP_001334649.1
	COCH	NM_001135058.2		c.1348A>G	p.Ile450Val	missense	Exon 10 of 11	NP_001128530.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COCH	ENST00000396618.9	TSL:1 MANE Select	c.1348A>G	p.Ile450Val	missense	Exon 11 of 12	ENSP00000379862.3
	COCH	ENST00000216361.9	TSL:1	c.1543A>G	p.Ile515Val	missense	Exon 10 of 11	ENSP00000216361.5
	COCH	ENST00000475087.5	TSL:1	c.1348A>G	p.Ile450Val	missense	Exon 10 of 11	ENSP00000451528.1

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000879 AC: 220 AN: 250148 AF XY: 0.000888

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000581

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.000736 AC: 1074 AN: 1458292 Hom.: 3 Cov.: 34 AF XY: 0.000766 AC XY: 555 AN XY: 724766

African (AFR) AF: 0.0000300 AC: 1 AN: 33338

American (AMR) AF: 0.000494 AC: 22 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.000557 AC: 48 AN: 86124

European-Finnish (FIN) AF: 0.00111 AC: 59 AN: 53360

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5752

European-Non Finnish (NFE) AF: 0.000782 AC: 867 AN: 1109360

Other (OTH) AF: 0.000897 AC: 54 AN: 60192

GnomAD4 genome AF: 0.000853 AC: 130 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000900 AC XY: 67 AN XY: 74476

African (AFR) AF: 0.000241 AC: 10 AN: 41576

American (AMR) AF: 0.00177 AC: 27 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68038

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000808

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000799 AC: 97

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 05, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile450Val variant (rs139503327) has not been reported in the medical literature, or gene specific variation databases but has been reported to ClinVar (Variation ID:228523). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.08 percent (identified on 244 out of 275,816 chromosomes including 2 homozygotes). The isoleucine at position 450 is highly conserved up to Zebrafish (considering 12 species) (Alamut v2.10.0) and computational analyses of the effects of the p.Ile450Val variant on protein structure and function provide conflicting results (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Ile450Val variant with certainty.

not specified Benign:2

Oct 09, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile450Val variant in COCH is classified as benign because it has been iden tified in 0.1% (149/126048) of European chromosomes by gnomAD (http://gnomad.bro adinstitute.org). Furthermore, isoleucine (Ile) at position 450 is not highly co nserved in mammals, and one mammal (platypus) carries a valine (Val), supporting that this change may be tolerated. ACMG/AMP Criteria applied: BA1, BP4.

Sep 01, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal dominant nonsyndromic hearing loss 9 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.056	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.93	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.020	D
Sift4G	Benign	0.12	T
Polyphen		0.0040	B
Vest4		0.41
MVP		0.70
MPC		0.19
ClinPred		0.051	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.63
Mutation Taster		=85/15	polymorphism

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: rs139503327; hg19: chr14-31355389;