rs942519

Variant names:

• chr9-114406753-A-G
• rs942519
• NM_015404.4:c.1838T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-114406753-A-G
• chr9-114406753-A-T

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.1838T>C​(p.Met613Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 1,613,758 control chromosomes in the GnomAD database, including 234,027 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M613R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.49 (18272 hom., cov: 32)
  • Exomes 𝑓: 0.54 (215755 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.24
• Publications: 45 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=6.9923813E-6).
• BP6: Variant 9-114406753-A-G is Benign according to our data. Variant chr9-114406753-A-G is described in ClinVar as Benign. ClinVar VariationId is 45663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.561 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	NM_015404.4	MANE Select	c.1838T>C	p.Met613Thr	missense	Exon 9 of 12	NP_056219.3
	WHRN	NM_001173425.2		c.1838T>C	p.Met613Thr	missense	Exon 9 of 12	NP_001166896.1
	WHRN	NM_001346890.1		c.785T>C	p.Met262Thr	missense	Exon 5 of 8	NP_001333819.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	ENST00000362057.4	TSL:1 MANE Select	c.1838T>C	p.Met613Thr	missense	Exon 9 of 12	ENSP00000354623.3
	WHRN	ENST00000265134.10	TSL:1	c.689T>C	p.Met230Thr	missense	Exon 9 of 12	ENSP00000265134.6
	WHRN	ENST00000866780.1		c.1838T>C	p.Met613Thr	missense	Exon 9 of 12	ENSP00000536839.1

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73752 AN: 151974 Hom.: 18256 Cov.: 32

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.570

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.500

GnomAD2 exomes AF: 0.529 AC: 132256 AN: 249862 AF XY: 0.536

Gnomad AFR exome AF: 0.360

Gnomad AMR exome AF: 0.520

Gnomad ASJ exome AF: 0.607

Gnomad EAS exome AF: 0.499

Gnomad FIN exome AF: 0.494

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.533

GnomAD4 exome AF: 0.542 AC: 791630 AN: 1461664 Hom.: 215755 Cov.: 99 AF XY: 0.544 AC XY: 395471 AN XY: 727110

African (AFR) AF: 0.359 AC: 12020 AN: 33480

American (AMR) AF: 0.519 AC: 23192 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 15798 AN: 26132

East Asian (EAS) AF: 0.536 AC: 21281 AN: 39692

South Asian (SAS) AF: 0.596 AC: 51369 AN: 86242

European-Finnish (FIN) AF: 0.493 AC: 26316 AN: 53354

Middle Eastern (MID) AF: 0.570 AC: 3285 AN: 5764

European-Non Finnish (NFE) AF: 0.545 AC: 606210 AN: 1111936

Other (OTH) AF: 0.533 AC: 32159 AN: 60390

GnomAD4 genome AF: 0.485 AC: 73800 AN: 152094 Hom.: 18272 Cov.: 32 AF XY: 0.482 AC XY: 35876 AN XY: 74356

African (AFR) AF: 0.364 AC: 15098 AN: 41482

American (AMR) AF: 0.494 AC: 7554 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2126 AN: 3470

East Asian (EAS) AF: 0.505 AC: 2601 AN: 5148

South Asian (SAS) AF: 0.579 AC: 2793 AN: 4826

European-Finnish (FIN) AF: 0.491 AC: 5205 AN: 10594

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.540 AC: 36694 AN: 67966

Other (OTH) AF: 0.495 AC: 1045 AN: 2112

Alfa AF: 0.526 Hom.: 54813

Bravo AF: 0.482

TwinsUK AF: 0.546 AC: 2023

ALSPAC AF: 0.559 AC: 2156

ESP6500AA AF: 0.387 AC: 1703

ESP6500EA AF: 0.546 AC: 4695

ExAC AF: 0.529 AC: 64172

Asia WGS AF: 0.479 AC: 1667 AN: 3478

EpiCase AF: 0.541

EpiControl AF: 0.546

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 31 (2)
-	-	1	Usher syndrome type 2D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.4
DANN	Benign	0.18
DEOGEN2	Benign	0.047	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.019	T
MetaRNN	Benign	0.0000070	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.69	N
PhyloP100		1.2
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.054
Sift	Benign	0.53	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.014
MPC		0.14
ClinPred		0.0037	T
GERP RS		0.056
Varity_R		0.042
gMVP		0.17
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: rs942519; hg19: chr9-117169033; COSMIC: COSV54327986;