chr14-30875299-G-A

Variant names:

• chr14-30875299-G-A
• rs940268941
• NM_004086.3:c.82+196G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PVS1_Strong BS1

The NM_001347720.2(COCH):​c.277+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000716 in 810,588 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars). The gene COCH is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (1 hom.)
• Consequence: COCH NM_001347720.2 splice_donor, intron
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.208
• 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

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13149351 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000729 (48/658332) while in subpopulation EAS AF = 0.000371 (12/32318). AF 95% confidence interval is 0.000214. There are 1 homozygotes in GnomAdExome4. There are 25 alleles in the male GnomAdExome4 subpopulation. Median coverage is 8. This position passed quality control check.

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+196G>A		intron	N/A	NP_004077.1	O43405-1
	COCH	NM_001347720.2		c.277+1G>A		splice_donor intron	N/A	NP_001334649.1	A0A2U3TZE7
	COCH	NM_001135058.2		c.82+196G>A		intron	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.82+196G>A		intron	N/A	ENSP00000379862.3	O43405-1
	COCH	ENST00000216361.9	TSL:1	c.277+1G>A		splice_donor intron	N/A	ENSP00000216361.5	A0A2U3TZE7
	COCH	ENST00000475087.5	TSL:1	c.82+196G>A		intron	N/A	ENSP00000451528.1	O43405-2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.0000729 AC: 48 AN: 658332 Hom.: 1 Cov.: 8 AF XY: 0.0000738 AC XY: 25 AN XY: 338844

African (AFR) AF: 0.000183 AC: 3 AN: 16394

American (AMR) AF: 0.00 AC: 0 AN: 20512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15232

East Asian (EAS) AF: 0.000371 AC: 12 AN: 32318

South Asian (SAS) AF: 0.00 AC: 0 AN: 51254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2396

European-Non Finnish (NFE) AF: 0.00000219 AC: 1 AN: 457288

Other (OTH) AF: 0.000969 AC: 32 AN: 33014

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74388

African (AFR) AF: 0.0000482 AC: 2 AN: 41466

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000577 AC: 3 AN: 5198

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000125

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	COCH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.3
DANN	Benign	0.75
FATHMM_MKL	Benign	0.13	N
PhyloP100		0.21
GERP RS		-0.82
PromoterAI		0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 4

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

Other links and lift over

dbSNP: rs940268941; hg19: chr14-31344505;