chr14-30889763-G-T

Variant names:

• chr14-30889763-G-T
• rs121908932
• NM_004086.3:c.1625G>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004086.3(COCH):​c.1625G>T​(p.Cys542Phe) 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 (★★). ClinVar reports functional evidence for this variant: "SCV005397658: Studies examining the functional consequence of this variant have demonstrated that post-translational proteolytic processing is altered (PMID:16261627), and the variant protein has a decreased affinity for heparin (PMID:35901072)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C542Y) has been classified as Pathogenic. The gene COCH is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COCH NM_004086.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.49
• Publications: 21 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

Specifications for COCH are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005397658: Studies examining the functional consequence of this variant have demonstrated that post-translational proteolytic processing is altered (PMID: 16261627), and the variant protein has a decreased affinity for heparin (PMID: 35901072).; SCV001767763: Published functional studies demonstrate a damaging effect: reduced binding affinity to N-sulfated heparin (Honda et al., 2022); SCV002237040: Experimental studies have shown that this missense change affects COCH function (PMID: 16261627).
• 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-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6615.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 14-30889763-G-T is Pathogenic according to our data. Variant chr14-30889763-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COCH	NM_004086.3	MANE Select	c.1625G>T	p.Cys542Phe	missense	Exon 12 of 12	NP_004077.1	O43405-1
	COCH	NM_001347720.2		c.1820G>T	p.Cys607Phe	missense	Exon 11 of 11	NP_001334649.1	A0A2U3TZE7
	COCH	NM_001135058.2		c.1625G>T	p.Cys542Phe	missense	Exon 11 of 11	NP_001128530.1	O43405-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COCH	ENST00000396618.9	TSL:1 MANE Select	c.1625G>T	p.Cys542Phe	missense	Exon 12 of 12	ENSP00000379862.3	O43405-1
	COCH	ENST00000216361.9	TSL:1	c.1820G>T	p.Cys607Phe	missense	Exon 11 of 11	ENSP00000216361.5	A0A2U3TZE7
	COCH	ENST00000475087.5	TSL:1	c.1477+3451G>T		intron	N/A	ENSP00000451528.1	O43405-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Autosomal dominant nonsyndromic hearing loss 9 (3)
2	-	-	not provided (2)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-9.6	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.57	P
Vest4		0.95
MutPred		0.99		Gain of helix (P = 0.132)
MVP		0.93
MPC		1.0
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.96
gMVP		0.94
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs121908932; hg19: chr14-31358969;