9-114403926-G-T

Position:

• chr9-114403926-G-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 -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 id is 45674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-114403926-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4	c.2388C>A	p.Asn796Lys	missense_variant	10/12	ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4	c.2388C>A	p.Asn796Lys	missense_variant	10/12	1	NM_015404.4	P1

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

GnomAD3 exomes AF: 0.255 AC: 63508 AN: 249462 Hom.: 8864 AF XY: 0.252 AC XY: 34053 AN XY: 134980

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 SAS exome AF: 0.266

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

Gnomad4 AFR exome AF: 0.0650

Gnomad4 AMR exome AF: 0.360

Gnomad4 ASJ exome AF: 0.239

Gnomad4 EAS exome AF: 0.360

Gnomad4 SAS exome AF: 0.268

Gnomad4 FIN exome AF: 0.273

Gnomad4 NFE exome AF: 0.226

Gnomad4 OTH exome AF: 0.227

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

Gnomad4 AFR AF: 0.0739

Gnomad4 AMR AF: 0.277

Gnomad4 ASJ AF: 0.249

Gnomad4 EAS AF: 0.329

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.288

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.216

Alfa AF: 0.220 Hom.: 9181

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2009	- -

Autosomal recessive nonsyndromic hearing loss 31 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Usher syndrome type 2D Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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
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;T;T
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	.;.;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.52	N;N;N
REVEL	Benign	0.0050
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.77	T;T;T
Polyphen		0.023, 0.013	.;B;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

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: rs2274158; hg19: chr9-117166206; COSMIC: COSV54328256;