rs1045644

Variant names:

• chr14-30885890-C-G
• rs1045644
• NM_004086.3:c.1055C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004086.3(COCH):​c.1055C>G​(p.Thr352Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 1,613,614 control chromosomes in the GnomAD database, including 295,272 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (22153 hom., cov: 33)
  • Exomes 𝑓: 0.60 (273119 hom.)
• Consequence: COCH NM_004086.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.97
• Publications: 55 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=1.766174E-5).
• BP6: Variant 14-30885890-C-G is Benign according to our data. Variant chr14-30885890-C-G is described in ClinVar as Benign. ClinVar VariationId is 226525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

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.1055C>G	p.Thr352Ser	missense	Exon 11 of 12	NP_004077.1	O43405-1
	COCH	NM_001347720.2		c.1250C>G	p.Thr417Ser	missense	Exon 10 of 11	NP_001334649.1	A0A2U3TZE7
	COCH	NM_001135058.2		c.1055C>G	p.Thr352Ser	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.1055C>G	p.Thr352Ser	missense	Exon 11 of 12	ENSP00000379862.3	O43405-1
	COCH	ENST00000216361.9	TSL:1	c.1250C>G	p.Thr417Ser	missense	Exon 10 of 11	ENSP00000216361.5	A0A2U3TZE7
	COCH	ENST00000475087.5	TSL:1	c.1055C>G	p.Thr352Ser	missense	Exon 10 of 11	ENSP00000451528.1	O43405-2

Frequencies

GnomAD3 genomes AF: 0.514 AC: 78143 AN: 152032 Hom.: 22143 Cov.: 33

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.662

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.545

GnomAD2 exomes AF: 0.558 AC: 140099 AN: 251088 AF XY: 0.553

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.649

Gnomad ASJ exome AF: 0.598

Gnomad EAS exome AF: 0.360

Gnomad FIN exome AF: 0.652

Gnomad NFE exome AF: 0.635

Gnomad OTH exome AF: 0.595

GnomAD4 exome AF: 0.603 AC: 880660 AN: 1461464 Hom.: 273119 Cov.: 49 AF XY: 0.596 AC XY: 433266 AN XY: 727036

African (AFR) AF: 0.254 AC: 8510 AN: 33476

American (AMR) AF: 0.645 AC: 28845 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 15548 AN: 26130

East Asian (EAS) AF: 0.334 AC: 13257 AN: 39692

South Asian (SAS) AF: 0.362 AC: 31192 AN: 86246

European-Finnish (FIN) AF: 0.645 AC: 34474 AN: 53410

Middle Eastern (MID) AF: 0.550 AC: 3171 AN: 5768

European-Non Finnish (NFE) AF: 0.640 AC: 711589 AN: 1111650

Other (OTH) AF: 0.564 AC: 34074 AN: 60374

GnomAD4 genome AF: 0.514 AC: 78167 AN: 152150 Hom.: 22153 Cov.: 33 AF XY: 0.513 AC XY: 38117 AN XY: 74374

African (AFR) AF: 0.273 AC: 11312 AN: 41502

American (AMR) AF: 0.608 AC: 9298 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 2080 AN: 3472

East Asian (EAS) AF: 0.348 AC: 1803 AN: 5180

South Asian (SAS) AF: 0.350 AC: 1688 AN: 4818

European-Finnish (FIN) AF: 0.662 AC: 6998 AN: 10570

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.633 AC: 43035 AN: 68000

Other (OTH) AF: 0.540 AC: 1139 AN: 2110

Alfa AF: 0.605 Hom.: 21510

Bravo AF: 0.505

TwinsUK AF: 0.625 AC: 2318

ALSPAC AF: 0.649 AC: 2502

ESP6500AA AF: 0.282 AC: 1244

ESP6500EA AF: 0.630 AC: 5415

ExAC AF: 0.549 AC: 66605

Asia WGS AF: 0.337 AC: 1174 AN: 3478

EpiCase AF: 0.624

EpiControl AF: 0.625

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Autosomal dominant nonsyndromic hearing loss 9 (4)
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Hearing loss, autosomal recessive 110 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.000018	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.0	N
PhyloP100		2.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.23
Sift	Benign	0.034	D
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.048
MutPred		0.13		Gain of helix (P = 0.062)
MPC		0.19
ClinPred		0.0024	T
GERP RS		4.2
Varity_R		0.053
gMVP		0.16
Mutation Taster		=99/1	polymorphism (auto)

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: rs1045644; hg19: chr14-31355096; COSMIC: COSV53549551; COSMIC: COSV53549551;