rs121908933

chr14-30889763-G-Achr14-30889763-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_004086.3(COCH):c.1625G>A(p.Cys542Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C542F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COCH NM_004086.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.49

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-30889763-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 6614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 14-30889763-G-A is Pathogenic according to our data. Variant chr14-30889763-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6615.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-30889763-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COCH	NM_004086.3	c.1625G>A	p.Cys542Tyr	missense_variant	12/12	ENST00000396618.9
LOC100506071	NR_038356.1	n.46C>T		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COCH	ENST00000396618.9	c.1625G>A	p.Cys542Tyr	missense_variant	12/12	1	NM_004086.3	P1
	ENST00000555108.1	n.46C>T		non_coding_transcript_exon_variant	1/5	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 9 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;.;.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Benign	-0.40	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
REVEL	Pathogenic	0.83
Polyphen		0.80	.;P;P;.;P
Vest4		0.96, 0.98
MutPred		0.98		.;Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);.;Gain of disorder (P = 0.0961);
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.94

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: rs121908932; hg19: chr14-31358969;