rs55833018

Variant names:

• chr9-114403457-C-T
• rs55833018
• NM_015404.4:c.2419-118G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015404.4(WHRN):​c.2419-118G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 1,391,338 control chromosomes in the GnomAD database, including 45,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (3672 hom., cov: 33)
  • Exomes 𝑓: 0.25 (41665 hom.)
• Consequence: WHRN NM_015404.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.59
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-114403457-C-T is Benign according to our data. Variant chr9-114403457-C-T is described in ClinVar as Benign. ClinVar VariationId is 1243163.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4	c.2419-118G>A		intron_variant	Intron 10 of 11	ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4	c.2419-118G>A		intron_variant	Intron 10 of 11	1	NM_015404.4	ENSP00000354623.3

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32269 AN: 152056 Hom.: 3673 Cov.: 33

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.229

GnomAD4 exome AF: 0.254 AC: 315115 AN: 1239164 Hom.: 41665 AF XY: 0.257 AC XY: 160624 AN XY: 625840

African (AFR) AF: 0.136 AC: 3934 AN: 28840

American (AMR) AF: 0.131 AC: 5610 AN: 42792

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 8747 AN: 24492

East Asian (EAS) AF: 0.144 AC: 5482 AN: 38158

South Asian (SAS) AF: 0.271 AC: 21880 AN: 80694

European-Finnish (FIN) AF: 0.198 AC: 10246 AN: 51636

Middle Eastern (MID) AF: 0.329 AC: 1359 AN: 4128

European-Non Finnish (NFE) AF: 0.267 AC: 244666 AN: 915576

Other (OTH) AF: 0.250 AC: 13191 AN: 52848

GnomAD4 genome AF: 0.212 AC: 32272 AN: 152174 Hom.: 3672 Cov.: 33 AF XY: 0.208 AC XY: 15457 AN XY: 74400

African (AFR) AF: 0.140 AC: 5829 AN: 41548

American (AMR) AF: 0.169 AC: 2592 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1219 AN: 3470

East Asian (EAS) AF: 0.138 AC: 711 AN: 5158

South Asian (SAS) AF: 0.254 AC: 1226 AN: 4818

European-Finnish (FIN) AF: 0.190 AC: 2011 AN: 10594

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.263 AC: 17844 AN: 67970

Other (OTH) AF: 0.226 AC: 478 AN: 2116

Alfa AF: 0.232 Hom.: 552

Bravo AF: 0.208

Asia WGS AF: 0.168 AC: 585 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.027
DANN	Benign	0.62
PhyloP100		-1.6
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: rs55833018; hg19: chr9-117165737;