9-114498554-C-T

Variant names:

• chr9-114498554-C-T
• rs10982256
• NM_015404.4:c.618+5630G>A

Variant summary

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

The NM_015404.4(WHRN):​c.618+5630G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 151,964 control chromosomes in the GnomAD database, including 15,353 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 0.41 (15353 hom., cov: 31)
• Consequence: WHRN NM_015404.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.55
• Publications: 14 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4	c.618+5630G>A		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.618+5630G>A		intron_variant	Intron 1 of 11	1	NM_015404.4	ENSP00000354623.3

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62393 AN: 151848 Hom.: 15352 Cov.: 31

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.452

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.450

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

GnomAD4 genome AF: 0.411 AC: 62397 AN: 151964 Hom.: 15353 Cov.: 31 AF XY: 0.409 AC XY: 30395 AN XY: 74228

African (AFR) AF: 0.121 AC: 5035 AN: 41504

American (AMR) AF: 0.433 AC: 6616 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 1622 AN: 3462

East Asian (EAS) AF: 0.584 AC: 3009 AN: 5154

South Asian (SAS) AF: 0.523 AC: 2511 AN: 4798

European-Finnish (FIN) AF: 0.460 AC: 4845 AN: 10532

Middle Eastern (MID) AF: 0.483 AC: 141 AN: 292

European-Non Finnish (NFE) AF: 0.548 AC: 37256 AN: 67940

Other (OTH) AF: 0.452 AC: 952 AN: 2108

Alfa AF: 0.486 Hom.: 39064

Bravo AF: 0.394

Asia WGS AF: 0.516 AC: 1794 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.0060
DANN	Benign	0.56
PhyloP100		-2.5
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: rs10982256; hg19: chr9-117260834; COSMIC: COSV54329215; COSMIC: COSV54329215;