rs28362778

Variant names:

• chr14-30886039-A-G
• rs28362778
• NM_004086.3:c.1204A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-30886039-A-G
• chr14-30886039-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004086.3(COCH):​c.1204A>G​(p.Ile402Val) variant causes a missense change. The variant allele was found at a frequency of 0.000304 in 1,614,230 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I402T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: COCH NM_004086.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.22
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00884366).
• BP6: Variant 14-30886039-A-G is Benign according to our data. Variant chr14-30886039-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 313004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00152 (232/152340) while in subpopulation AFR AF = 0.00544 (226/41570). AF 95% confidence interval is 0.00486. There are 2 homozygotes in GnomAd4. There are 126 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.1204A>G	p.Ile402Val	missense	Exon 11 of 12	NP_004077.1	O43405-1
	COCH	NM_001347720.2		c.1399A>G	p.Ile467Val	missense	Exon 10 of 11	NP_001334649.1	A0A2U3TZE7
	COCH	NM_001135058.2		c.1204A>G	p.Ile402Val	missense	Exon 10 of 11	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.1204A>G	p.Ile402Val	missense	Exon 11 of 12	ENSP00000379862.3	O43405-1
	COCH	ENST00000216361.9	TSL:1	c.1399A>G	p.Ile467Val	missense	Exon 10 of 11	ENSP00000216361.5	A0A2U3TZE7
	COCH	ENST00000475087.5	TSL:1	c.1204A>G	p.Ile402Val	missense	Exon 10 of 11	ENSP00000451528.1	O43405-2

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 229 AN: 152222 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00538

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000493 AC: 124 AN: 251444 AF XY: 0.000324

Gnomad AFR exome AF: 0.00683

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000176 AC: 258 AN: 1461890 Hom.: 2 Cov.: 34 AF XY: 0.000143 AC XY: 104 AN XY: 727248

African (AFR) AF: 0.00639 AC: 214 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112008

Other (OTH) AF: 0.000381 AC: 23 AN: 60396

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152340 Hom.: 2 Cov.: 33 AF XY: 0.00169 AC XY: 126 AN XY: 74494

African (AFR) AF: 0.00544 AC: 226 AN: 41570

American (AMR) AF: 0.000131 AC: 2 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000454 Hom.: 0

Bravo AF: 0.00162

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000527 AC: 64

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Autosomal dominant nonsyndromic hearing loss 9 (1)
-	-	1	COCH-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.080
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.090	N
PhyloP100		5.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.42	N
REVEL	Uncertain	0.33
Sift	Benign	0.31	T
Sift4G	Benign	0.76	T
Polyphen		0.061	B
Vest4		0.15
MVP		0.64
MPC		0.18
ClinPred		0.026	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.29
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs28362778; hg19: chr14-31355245;