rs28400022

Variant names:

• chr14-30874744-T-G
• rs28400022
• ENST00000216361.9:c.-195T>G

Variant summary

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

The NM_001347720.2(COCH):​c.-195T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 659,338 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (6 hom.)
• Consequence: COCH NM_001347720.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0100
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 14-30874744-T-G is Benign according to our data. Variant chr14-30874744-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1211320.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 = 0.00861 (1311/152238) while in subpopulation AFR AF = 0.0297 (1236/41564). AF 95% confidence interval is 0.0284. There are 12 homozygotes in GnomAd4. There are 608 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347720.2. 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.-24+153T>G		intron	N/A	NP_004077.1	O43405-1
	COCH	NM_001347720.2		c.-195T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001334649.1	A0A2U3TZE7
	COCH	NM_001135058.2		c.-195T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001128530.1	O43405-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COCH	ENST00000216361.9	TSL:1	c.-195T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000216361.5	A0A2U3TZE7
	COCH	ENST00000475087.5	TSL:1	c.-195T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000451528.1	O43405-2
	COCH	ENST00000216361.9	TSL:1	c.-195T>G		5_prime_UTR	Exon 1 of 11	ENSP00000216361.5	A0A2U3TZE7

Frequencies

GnomAD3 genomes AF: 0.00857 AC: 1304 AN: 152120 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00134 AC: 682 AN: 507100 Hom.: 6 Cov.: 6 AF XY: 0.00105 AC XY: 283 AN XY: 268618

African (AFR) AF: 0.0332 AC: 471 AN: 14206

American (AMR) AF: 0.00202 AC: 50 AN: 24774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15030

East Asian (EAS) AF: 0.00 AC: 0 AN: 31694

South Asian (SAS) AF: 0.000139 AC: 7 AN: 50460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30656

Middle Eastern (MID) AF: 0.00597 AC: 13 AN: 2178

European-Non Finnish (NFE) AF: 0.000139 AC: 43 AN: 309946

Other (OTH) AF: 0.00348 AC: 98 AN: 28156

GnomAD4 genome AF: 0.00861 AC: 1311 AN: 152238 Hom.: 12 Cov.: 33 AF XY: 0.00817 AC XY: 608 AN XY: 74438

African (AFR) AF: 0.0297 AC: 1236 AN: 41564

American (AMR) AF: 0.00314 AC: 48 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67992

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00858 Hom.: 11

Bravo AF: 0.00964

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.3
DANN	Benign	0.50
PhyloP100		-0.010
PromoterAI		0.090	Neutral
Mutation Taster		=300/0	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: rs28400022; hg19: chr14-31343950;