chr14-30874865-G-T

Variant names:

• chr14-30874865-G-T
• rs78284050
• ENST00000216361.9:c.-74G>T

Variant summary

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

The NM_001347720.2(COCH):​c.-74G>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 0.00000142 in 1,406,806 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COCH NM_001347720.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.149
• 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=-0.7).

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.-23-51G>T		intron	N/A	NP_004077.1	O43405-1
	COCH	NM_001347720.2		c.-74G>T		5_prime_UTR	Exon 1 of 11	NP_001334649.1	A0A2U3TZE7
	COCH	NM_001135058.2		c.-74G>T		5_prime_UTR	Exon 1 of 11	NP_001128530.1	O43405-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COCH	ENST00000216361.9	TSL:1	c.-74G>T		5_prime_UTR	Exon 1 of 11	ENSP00000216361.5	A0A2U3TZE7
	COCH	ENST00000475087.5	TSL:1	c.-74G>T		5_prime_UTR	Exon 1 of 11	ENSP00000451528.1	O43405-2
	COCH	ENST00000396618.9	TSL:1 MANE Select	c.-23-51G>T		intron	N/A	ENSP00000379862.3	O43405-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1406806 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 702898

African (AFR) AF: 0.00 AC: 0 AN: 32330

American (AMR) AF: 0.00 AC: 0 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25752

East Asian (EAS) AF: 0.00 AC: 0 AN: 39404

South Asian (SAS) AF: 0.00 AC: 0 AN: 85182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1063678

Other (OTH) AF: 0.00 AC: 0 AN: 58612

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.9
DANN	Benign	0.73
PhyloP100		-0.15
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs78284050; hg19: chr14-31344071;