Genetic Variant ENST00000216361:c.-74G>A (chr14-30874865-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000216361.9(COCH):c.-74G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,558,958 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 11 hom. )

Consequence

COCH
ENST00000216361.9 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.149

Publications

0 publications found

Variant links:

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

COCH links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 14-30874865-G-A is Benign according to our data. Variant chr14-30874865-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1211708.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 = 0.00568 (865/152162) while in subpopulation AFR AF = 0.0175 (725/41522). AF 95% confidence interval is 0.0164. There are 3 homozygotes in GnomAd4. There are 434 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COCH	NM_004086.3	MANE Select	c.-23-51G>A	intron	N/A	NP_004077.1	O43405-1
COCH	NM_001347720.2		c.-74G>A	5_prime_UTR	Exon 1 of 11	NP_001334649.1	A0A2U3TZE7
COCH	NM_001135058.2		c.-74G>A	5_prime_UTR	Exon 1 of 11	NP_001128530.1	O43405-1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.00566

AC:

860

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000662

Gnomad OTH

AF:

0.00383

GnomAD4 exome

AF:

0.00106

AC:

1488

AN:

1406796

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

716

AN XY:

702894

show subpopulations

African (AFR)

AF:

0.0187

AC:

606

AN:

32322

American (AMR)

AF:

0.00238

AC:

106

AN:

44600

Ashkenazi Jewish (ASJ)

AF:

0.00478

AC:

123

AN:

25752

East Asian (EAS)

AF:

0.00

AC:

AN:

39404

South Asian (SAS)

AF:

0.0000235

AC:

AN:

85182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51590

Middle Eastern (MID)

AF:

0.00318

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.000466

AC:

496

AN:

1063676

Other (OTH)

AF:

0.00234

AC:

137

AN:

58612

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

185

278

370

463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00568

AC:

865

AN:

152162

Hom.:

Cov.:

AF XY:

0.00583

AC XY:

434

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0175

AC:

725

AN:

41522

American (AMR)

AF:

0.00471

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000662

AC:

AN:

67986

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

129

172

215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00395

Hom.:

Bravo

AF:

0.00660

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

-0.15

PromoterAI

-0.036

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=300/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over