9-114488113-A-G

Variant names:

• chr9-114488113-A-G
• rs10982246
• NM_015404.4:c.619-9342T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015404.4(WHRN):​c.619-9342T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 152,074 control chromosomes in the GnomAD database, including 14,283 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (14283 hom., cov: 32)
• Consequence: WHRN NM_015404.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0220
• Publications: 9 publications found

Genes affected

WHRN (HGNC:16361): (whirlin) This gene is thought to function in the organization and stabilization of sterocilia elongation and actin cystoskeletal assembly, based on studies of the related mouse gene. Mutations in this gene have been associated with autosomal recessive non-syndromic deafness and Usher Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

WHRN Gene-Disease associations (from GenCC):

• Usher syndrome type 2D

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• autosomal recessive nonsyndromic hearing loss 31

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4	c.619-9342T>C		intron_variant	Intron 1 of 11	ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4	c.619-9342T>C		intron_variant	Intron 1 of 11	1	NM_015404.4	ENSP00000354623.3

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60090 AN: 151956 Hom.: 14284 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.528

Gnomad OTH AF: 0.447

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.395 AC: 60090 AN: 152074 Hom.: 14283 Cov.: 32 AF XY: 0.393 AC XY: 29241 AN XY: 74312

African (AFR) AF: 0.115 AC: 4777 AN: 41508

American (AMR) AF: 0.431 AC: 6580 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1648 AN: 3472

East Asian (EAS) AF: 0.587 AC: 3039 AN: 5174

South Asian (SAS) AF: 0.543 AC: 2612 AN: 4812

European-Finnish (FIN) AF: 0.387 AC: 4085 AN: 10562

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.528 AC: 35859 AN: 67958

Other (OTH) AF: 0.449 AC: 950 AN: 2114

Alfa AF: 0.478 Hom.: 14284

Bravo AF: 0.384

Asia WGS AF: 0.522 AC: 1814 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.68
PhyloP100		-0.022
Mutation Taster		=100/0	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: rs10982246; hg19: chr9-117250393; COSMIC: COSV54329121; COSMIC: COSV54329121;