ENST00000216361.9:c.258G>A

Variant names:

• chr14-30875279-G-A
• ENST00000216361.9:c.258G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The ENST00000216361.9(COCH):​c.258G>A​(p.Leu86Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L86L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COCH ENST00000216361.9 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.177
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 14-30875279-G-A is Benign according to our data. Variant chr14-30875279-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3251070.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.177 with no splicing effect.

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.82+176G>A		intron	N/A	NP_004077.1	O43405-1
	COCH	NM_001347720.2		c.258G>A	p.Leu86Leu	synonymous	Exon 2 of 11	NP_001334649.1	A0A2U3TZE7
	COCH	NM_001135058.2		c.82+176G>A		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.258G>A	p.Leu86Leu	synonymous	Exon 2 of 11	ENSP00000216361.5	A0A2U3TZE7
	COCH	ENST00000396618.9	TSL:1 MANE Select	c.82+176G>A		intron	N/A	ENSP00000379862.3	O43405-1
	COCH	ENST00000475087.5	TSL:1	c.82+176G>A		intron	N/A	ENSP00000451528.1	O43405-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 739336 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 377478

African (AFR) AF: 0.00 AC: 0 AN: 18200

American (AMR) AF: 0.00 AC: 0 AN: 22642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16086

East Asian (EAS) AF: 0.00 AC: 0 AN: 32710

South Asian (SAS) AF: 0.00 AC: 0 AN: 53918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2582

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 527438

Other (OTH) AF: 0.00 AC: 0 AN: 35684

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.6
DANN	Benign	0.87
PhyloP100		-0.18
PromoterAI		-0.0020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

hg19: chr14-31344485;