NM_015404.4:c.2388C>A

Variant names:

• chr9-114403926-G-T
• rs2274158
• NM_015404.4:c.2388C>A

Variant summary

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

The NM_015404.4(WHRN):​c.2388C>A​(p.Asn796Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,610,268 control chromosomes in the GnomAD database, including 45,475 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N796N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (3552 hom., cov: 32)
  • Exomes 𝑓: 0.23 (41923 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.21
• Publications: 38 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041309297).
• BP6: Variant 9-114403926-G-T is Benign according to our data. Variant chr9-114403926-G-T is described in ClinVar as Benign. ClinVar VariationId is 45674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015404.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	NM_015404.4	MANE Select	c.2388C>A	p.Asn796Lys	missense	Exon 10 of 12	NP_056219.3
	WHRN	NM_001173425.2		c.2385C>A	p.Asn795Lys	missense	Exon 10 of 12	NP_001166896.1
	WHRN	NM_001346890.1		c.1335C>A	p.Asn445Lys	missense	Exon 6 of 8	NP_001333819.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	ENST00000362057.4	TSL:1 MANE Select	c.2388C>A	p.Asn796Lys	missense	Exon 10 of 12	ENSP00000354623.3
	WHRN	ENST00000265134.10	TSL:1	c.1239C>A	p.Asn413Lys	missense	Exon 10 of 12	ENSP00000265134.6
	WHRN	ENST00000674036.9		c.2178C>A	p.Asn726Lys	missense	Exon 9 of 11	ENSP00000501297.5

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30360 AN: 151914 Hom.: 3546 Cov.: 32

Gnomad AFR AF: 0.0740

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.218

GnomAD2 exomes AF: 0.255 AC: 63508 AN: 249462 AF XY: 0.252

Gnomad AFR exome AF: 0.0714

Gnomad AMR exome AF: 0.370

Gnomad ASJ exome AF: 0.236

Gnomad EAS exome AF: 0.334

Gnomad FIN exome AF: 0.272

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.237

GnomAD4 exome AF: 0.234 AC: 341502 AN: 1458234 Hom.: 41923 Cov.: 57 AF XY: 0.235 AC XY: 170635 AN XY: 725572

African (AFR) AF: 0.0650 AC: 2177 AN: 33472

American (AMR) AF: 0.360 AC: 16098 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 6244 AN: 26132

East Asian (EAS) AF: 0.360 AC: 14293 AN: 39694

South Asian (SAS) AF: 0.268 AC: 23148 AN: 86250

European-Finnish (FIN) AF: 0.273 AC: 13683 AN: 50166

Middle Eastern (MID) AF: 0.218 AC: 1255 AN: 5766

European-Non Finnish (NFE) AF: 0.226 AC: 250909 AN: 1111666

Other (OTH) AF: 0.227 AC: 13695 AN: 60364

GnomAD4 genome AF: 0.200 AC: 30380 AN: 152034 Hom.: 3552 Cov.: 32 AF XY: 0.203 AC XY: 15118 AN XY: 74308

African (AFR) AF: 0.0739 AC: 3066 AN: 41510

American (AMR) AF: 0.277 AC: 4234 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 865 AN: 3468

East Asian (EAS) AF: 0.329 AC: 1687 AN: 5128

South Asian (SAS) AF: 0.263 AC: 1264 AN: 4810

European-Finnish (FIN) AF: 0.288 AC: 3044 AN: 10576

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15517 AN: 67952

Other (OTH) AF: 0.216 AC: 457 AN: 2112

Alfa AF: 0.215 Hom.: 12374

Bravo AF: 0.195

TwinsUK AF: 0.227 AC: 842

ALSPAC AF: 0.248 AC: 955

ESP6500AA AF: 0.0801 AC: 353

ESP6500EA AF: 0.231 AC: 1987

ExAC AF: 0.247 AC: 30044

Asia WGS AF: 0.245 AC: 850 AN: 3478

EpiCase AF: 0.226

EpiControl AF: 0.222

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

not specified Benign:2

Jun 19, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive nonsyndromic hearing loss 31 Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Retinitis pigmentosa-deafness syndrome Benign:1

May 28, 2019

Mendelics

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.0010
DANN	Benign	0.66
DEOGEN2	Benign	0.076	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L
PhyloP100		-3.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.0050
Sift	Benign	0.32	T
Sift4G	Benign	0.77	T
Polyphen		0.023	B
Vest4		0.12
MutPred		0.36		Gain of methylation at N796 (P = 0.0091)
MPC		0.14
ClinPred		0.0055	T
GERP RS		-7.5
Varity_R		0.045
gMVP		0.16
Mutation Taster		=98/2	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: rs2274158; hg19: chr9-117166206; COSMIC: COSV54328256;