rs886050442

Variant names:

• chr14-30874549-C-T
• rs886050442
• ENST00000216361.9:c.-390C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000216361.9(COCH):​c.-390C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000426 in 234,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: COCH ENST00000216361.9 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.328
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000216361.9. 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.-66C>T		upstream_gene	N/A	NP_004077.1	O43405-1
	COCH	NM_001347720.2		c.-390C>T		upstream_gene	N/A	NP_001334649.1	A0A2U3TZE7
	COCH	NM_001135058.2		c.-390C>T		upstream_gene	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.-390C>T		5_prime_UTR	Exon 1 of 11	ENSP00000216361.5	A0A2U3TZE7
	COCH	ENST00000914779.1		c.-66C>T		5_prime_UTR	Exon 1 of 12	ENSP00000584838.1
	COCH	ENST00000914778.1		c.-390C>T		5_prime_UTR	Exon 1 of 12	ENSP00000584837.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000426 AC: 1 AN: 234888 Hom.: 0 Cov.: 0 AF XY: 0.00000802 AC XY: 1 AN XY: 124738

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 5218

American (AMR) AF: 0.00 AC: 0 AN: 9888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6634

East Asian (EAS) AF: 0.00 AC: 0 AN: 11344

South Asian (SAS) AF: 0.00 AC: 0 AN: 35222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1028

European-Non Finnish (NFE) AF: 0.00000712 AC: 1 AN: 140540

Other (OTH) AF: 0.00 AC: 0 AN: 13118

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Nonsyndromic Hearing Loss, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.4
DANN	Benign	0.93
PhyloP100		0.33
PromoterAI		-0.29	Neutral

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: rs886050442; hg19: chr14-31343755;