14-30874833-A-G

Variant names:

• chr14-30874833-A-G
• rs11555426
• ENST00000216361.9:c.-106A>G

Variant summary

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

The NM_001347720.2(COCH):​c.-106A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,325,606 control chromosomes in the GnomAD database, including 9,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1006 hom., cov: 33)
  • Exomes 𝑓: 0.12 (8418 hom.)
• Consequence: COCH NM_001347720.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.671
• Publications: 7 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=-0.76).
• BP6: Variant 14-30874833-A-G is Benign according to our data. Variant chr14-30874833-A-G is described in ClinVar as Benign. ClinVar VariationId is 682803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

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.-23-83A>G		intron	N/A	NP_004077.1	O43405-1
	COCH	NM_001347720.2		c.-106A>G		5_prime_UTR	Exon 1 of 11	NP_001334649.1	A0A2U3TZE7
	COCH	NM_001135058.2		c.-106A>G		5_prime_UTR	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.-106A>G		5_prime_UTR	Exon 1 of 11	ENSP00000216361.5	A0A2U3TZE7
	COCH	ENST00000475087.5	TSL:1	c.-106A>G		5_prime_UTR	Exon 1 of 11	ENSP00000451528.1	O43405-2
	COCH	ENST00000396618.9	TSL:1 MANE Select	c.-23-83A>G		intron	N/A	ENSP00000379862.3	O43405-1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17025 AN: 151826 Hom.: 1004 Cov.: 33

Gnomad AFR AF: 0.0943

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.0919

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0937

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.123

GnomAD4 exome AF: 0.117 AC: 137616 AN: 1173662 Hom.: 8418 Cov.: 17 AF XY: 0.118 AC XY: 70460 AN XY: 596596

African (AFR) AF: 0.0929 AC: 2577 AN: 27752

American (AMR) AF: 0.0727 AC: 3190 AN: 43876

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 3677 AN: 24132

East Asian (EAS) AF: 0.0803 AC: 3077 AN: 38330

South Asian (SAS) AF: 0.118 AC: 9464 AN: 80260

European-Finnish (FIN) AF: 0.103 AC: 4901 AN: 47656

Middle Eastern (MID) AF: 0.152 AC: 768 AN: 5068

European-Non Finnish (NFE) AF: 0.122 AC: 103999 AN: 855582

Other (OTH) AF: 0.117 AC: 5963 AN: 51006

GnomAD4 genome AF: 0.112 AC: 17031 AN: 151944 Hom.: 1006 Cov.: 33 AF XY: 0.112 AC XY: 8302 AN XY: 74290

African (AFR) AF: 0.0944 AC: 3911 AN: 41448

American (AMR) AF: 0.109 AC: 1663 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 510 AN: 3468

East Asian (EAS) AF: 0.0921 AC: 469 AN: 5094

South Asian (SAS) AF: 0.120 AC: 577 AN: 4818

European-Finnish (FIN) AF: 0.0937 AC: 991 AN: 10578

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8393 AN: 67938

Other (OTH) AF: 0.122 AC: 258 AN: 2112

Alfa AF: 0.113 Hom.: 1175

Bravo AF: 0.112

Asia WGS AF: 0.101 AC: 350 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.76
CADD	Benign	5.0
DANN	Benign	0.26
PhyloP100		-0.67
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11555426; hg19: chr14-31344039; COSMIC: COSV53550560; COSMIC: COSV53550560;