chr9-114504783-C-G

Variant names:

• chr9-114504783-C-G
• rs572671060
• NM_015404.4:c.19G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015404.4(WHRN):​c.19G>C​(p.Gly7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,459,668 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 34)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 1.22
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004876882).
• BP6: Variant 9-114504783-C-G is Benign according to our data. Variant chr9-114504783-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179353.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00135 (205/152292) while in subpopulation AFR AF = 0.00399 (166/41576). AF 95% confidence interval is 0.0035. There are 2 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.19G>C	p.Gly7Arg	missense	Exon 1 of 12	NP_056219.3
	WHRN	NM_001173425.2		c.19G>C	p.Gly7Arg	missense	Exon 1 of 12	NP_001166896.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	ENST00000362057.4	TSL:1 MANE Select	c.19G>C	p.Gly7Arg	missense	Exon 1 of 12	ENSP00000354623.3
	WHRN	ENST00000674036.9		c.19G>C	p.Gly7Arg	missense	Exon 1 of 11	ENSP00000501297.5
	WHRN	ENST00000699486.2		c.19G>C	p.Gly7Arg	missense	Exon 1 of 9	ENSP00000514397.2

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 207 AN: 152184 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00400

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000509 AC: 29 AN: 57026 AF XY: 0.000396

Gnomad AFR exome AF: 0.00459

Gnomad AMR exome AF: 0.000547

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000243

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.000284 AC: 371 AN: 1307376 Hom.: 0 Cov.: 34 AF XY: 0.000252 AC XY: 162 AN XY: 643190

African (AFR) AF: 0.00371 AC: 96 AN: 25888

American (AMR) AF: 0.000578 AC: 12 AN: 20762

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 54 AN: 20738

East Asian (EAS) AF: 0.00 AC: 0 AN: 30994

South Asian (SAS) AF: 0.0000745 AC: 5 AN: 67138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32480

Middle Eastern (MID) AF: 0.000262 AC: 1 AN: 3818

European-Non Finnish (NFE) AF: 0.000155 AC: 163 AN: 1051226

Other (OTH) AF: 0.000736 AC: 40 AN: 54332

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152292 Hom.: 2 Cov.: 34 AF XY: 0.00136 AC XY: 101 AN XY: 74470

African (AFR) AF: 0.00399 AC: 166 AN: 41576

American (AMR) AF: 0.000588 AC: 9 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000932 Hom.: 0

Bravo AF: 0.00160

ExAC AF: 0.000133 AC: 11

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Mar 12, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Jun 19, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive nonsyndromic hearing loss 31 Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Usher syndrome type 2D Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

not specified Benign:1

Nov 09, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gly7Arg in Exon 1 of DFNB31: This variant is not expected to have clinical signi ficance because the glycine (Gly) residue at position 7 is not conserved in seve ral species with wallaby, opossum, and platypus having an arginine (Arg) at that position.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.058
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.12	N
PhyloP100		1.2
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.68	N
REVEL	Benign	0.034
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.70	T
Polyphen		0.12	B
Vest4		0.19
MVP		0.27
MPC		1.8
ClinPred		0.067	T
GERP RS		4.1
Varity_R		0.29
gMVP		0.26
Mutation Taster		=66/34	polymorphism

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: rs572671060; hg19: chr9-117267063; COSMIC: COSV54332704; COSMIC: COSV54332704;