rs2297815

Variant names:

• chr9-114504685-C-T
• rs2297815
• NM_015404.4:c.117G>A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_015404.4(WHRN):​c.117G>A​(p.Val39Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,592,880 control chromosomes in the GnomAD database, including 100,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8605 hom., cov: 34)
  • Exomes 𝑓: 0.35 (92071 hom.)
• Consequence: WHRN NM_015404.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.584

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 9-114504685-C-T is Benign according to our data. Variant chr9-114504685-C-T is described in ClinVar as [Benign]. Clinvar id is 45644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-114504685-C-T is described in Lovd as [Likely_benign]. Variant chr9-114504685-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4	c.117G>A	p.Val39Val	synonymous_variant	Exon 1 of 12	ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4	c.117G>A	p.Val39Val	synonymous_variant	Exon 1 of 12	1	NM_015404.4	ENSP00000354623.3

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49598 AN: 152038 Hom.: 8609 Cov.: 34

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.325

GnomAD3 exomes AF: 0.326 AC: 69865 AN: 214404 Hom.: 11896 AF XY: 0.325 AC XY: 38523 AN XY: 118696

Gnomad AFR exome AF: 0.239

Gnomad AMR exome AF: 0.330

Gnomad ASJ exome AF: 0.359

Gnomad EAS exome AF: 0.141

Gnomad SAS exome AF: 0.227

Gnomad FIN exome AF: 0.494

Gnomad NFE exome AF: 0.371

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.353 AC: 508433 AN: 1440726 Hom.: 92071 Cov.: 40 AF XY: 0.350 AC XY: 250231 AN XY: 715960

Gnomad4 AFR exome AF: 0.227

Gnomad4 AMR exome AF: 0.326

Gnomad4 ASJ exome AF: 0.354

Gnomad4 EAS exome AF: 0.172

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.487

Gnomad4 NFE exome AF: 0.370

Gnomad4 OTH exome AF: 0.326

GnomAD4 genome AF: 0.326 AC: 49587 AN: 152154 Hom.: 8605 Cov.: 34 AF XY: 0.329 AC XY: 24498 AN XY: 74374

Gnomad4 AFR AF: 0.236

Gnomad4 AMR AF: 0.336

Gnomad4 ASJ AF: 0.344

Gnomad4 EAS AF: 0.139

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.507

Gnomad4 NFE AF: 0.372

Gnomad4 OTH AF: 0.321

Alfa AF: 0.356 Hom.: 2225

Bravo AF: 0.308

Asia WGS AF: 0.204 AC: 713 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

Jun 12, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 26, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 31 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 2D Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs2297815; hg19: chr9-117266965; COSMIC: COSV54328205; COSMIC: COSV54328205;