14-30875252-G-C

Variant names:

• chr14-30875252-G-C
• rs149627009
• ENST00000216361.9:c.231G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_001347720.2(COCH):​c.231G>C​(p.Ala77Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000986 in 1,115,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A77A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: COCH NM_001347720.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.14
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP7: Synonymous conserved (PhyloP=-2.14 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347720.2. 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.82+149G>C		intron	N/A	NP_004077.1	O43405-1
	COCH	NM_001347720.2		c.231G>C	p.Ala77Ala	synonymous	Exon 2 of 11	NP_001334649.1	A0A2U3TZE7
	COCH	NM_001135058.2		c.82+149G>C		intron	N/A	NP_001128530.1	O43405-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COCH	ENST00000216361.9	TSL:1	c.231G>C	p.Ala77Ala	synonymous	Exon 2 of 11	ENSP00000216361.5	A0A2U3TZE7
	COCH	ENST00000396618.9	TSL:1 MANE Select	c.82+149G>C		intron	N/A	ENSP00000379862.3	O43405-1
	COCH	ENST00000475087.5	TSL:1	c.82+149G>C		intron	N/A	ENSP00000451528.1	O43405-2

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 2 AN: 963022 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 483230

African (AFR) AF: 0.0000433 AC: 1 AN: 23112

American (AMR) AF: 0.00 AC: 0 AN: 28154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18580

East Asian (EAS) AF: 0.00 AC: 0 AN: 33684

South Asian (SAS) AF: 0.00 AC: 0 AN: 61424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3100

European-Non Finnish (NFE) AF: 0.00000139 AC: 1 AN: 720946

Other (OTH) AF: 0.00 AC: 0 AN: 43368

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74356

African (AFR) AF: 0.000217 AC: 9 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.012
DANN	Benign	0.77
PhyloP100		-2.1
PromoterAI		-0.0032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs149627009; hg19: chr14-31344458;