rs188655455

Variant names:

• chr14-30877251-T-C
• rs188655455
• NM_004086.3:c.83-321T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004086.3(COCH):​c.83-321T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 344,034 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: COCH NM_004086.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.640
• 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

ENSG00000258525 (HGNC:58454):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 14-30877251-T-C is Benign according to our data. Variant chr14-30877251-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1198065.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00334 (507/151914) while in subpopulation AFR AF = 0.0112 (464/41400). AF 95% confidence interval is 0.0104. There are 2 homozygotes in GnomAd4. There are 214 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004086.3. 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.83-321T>C		intron	N/A	NP_004077.1	O43405-1
	COCH	NM_001347720.2		c.278-321T>C		intron	N/A	NP_001334649.1	A0A2U3TZE7
	COCH	NM_001135058.2		c.83-321T>C		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.83-321T>C		intron	N/A	ENSP00000379862.3	O43405-1
	COCH	ENST00000216361.9	TSL:1	c.278-321T>C		intron	N/A	ENSP00000216361.5	A0A2U3TZE7
	COCH	ENST00000475087.5	TSL:1	c.83-321T>C		intron	N/A	ENSP00000451528.1	O43405-2

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 503 AN: 151796 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00385

GnomAD4 exome AF: 0.000442 AC: 85 AN: 192120 Hom.: 0 AF XY: 0.000349 AC XY: 36 AN XY: 103290

African (AFR) AF: 0.0106 AC: 61 AN: 5774

American (AMR) AF: 0.00105 AC: 9 AN: 8584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5014

East Asian (EAS) AF: 0.00 AC: 0 AN: 8716

South Asian (SAS) AF: 0.0000627 AC: 2 AN: 31916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 740

European-Non Finnish (NFE) AF: 0.0000976 AC: 11 AN: 112672

Other (OTH) AF: 0.000201 AC: 2 AN: 9954

GnomAD4 genome AF: 0.00334 AC: 507 AN: 151914 Hom.: 2 Cov.: 32 AF XY: 0.00288 AC XY: 214 AN XY: 74278

African (AFR) AF: 0.0112 AC: 464 AN: 41400

American (AMR) AF: 0.00151 AC: 23 AN: 15242

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67950

Other (OTH) AF: 0.00381 AC: 8 AN: 2102

Alfa AF: 0.00264 Hom.: 0

Bravo AF: 0.00420

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-1.0
CADD	Benign	1.9
DANN	Benign	0.19
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism

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: rs188655455; hg19: chr14-31346457;