14-30878834-GA-TT

Variant names:

• chr14-30878834-GA-TT
• NM_004086.3:c.263_264delGAinsTT
• COCH p.Gly88Val

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS1_Moderate PM1 PM5 PP3

The NM_004086.3(COCH):​c.263_264delGAinsTT​(p.Gly88Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G88E) has been classified as Likely pathogenic. The gene COCH is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COCH NM_004086.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.13
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PS1: Transcript NM_004086.3 (COCH) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_004086.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-30878834-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 6609.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.263_264delGAinsTT	p.Gly88Val	missense	N/A	NP_004077.1	O43405-1
	COCH	NM_001347720.2		c.458_459delGAinsTT	p.Gly153Val	missense	N/A	NP_001334649.1	A0A2U3TZE7
	COCH	NM_001135058.2		c.263_264delGAinsTT	p.Gly88Val	missense	N/A	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.263_264delGAinsTT	p.Gly88Val	missense	N/A	ENSP00000379862.3	O43405-1
	COCH	ENST00000216361.9	TSL:1	c.458_459delGAinsTT	p.Gly153Val	missense	N/A	ENSP00000216361.5	A0A2U3TZE7
	COCH	ENST00000475087.5	TSL:1	c.263_264delGAinsTT	p.Gly88Val	missense	N/A	ENSP00000451528.1	O43405-2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr14-31348040;