rs35258467

Variant names:

• chr9-114406545-C-G
• rs35258467
• NM_015404.4:c.2046G>C
• WHRN p.Arg682Arg

Your query was ambiguous. Multiple possible variants found:

• chr9-114406545-C-G
• chr9-114406545-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_015404.4(WHRN):​c.2046G>C​(p.Arg682Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000977 in 1,612,892 control chromosomes in the GnomAD database, including 14 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 0.0051 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (5 hom.)
• Consequence: WHRN NM_015404.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.0350
• Publications: 0 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: Unknown, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive nonsyndromic hearing loss 31

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.52).
• BP6: Variant 9-114406545-C-G is Benign according to our data. Variant chr9-114406545-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45665.
• BP7: Synonymous conserved (PhyloP=0.035 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00509 (775/152252) while in subpopulation AFR AF = 0.0173 (719/41552). AF 95% confidence interval is 0.0163. There are 9 homozygotes in GnomAd4. There are 357 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,Unknown 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	NM_015404.4	MANE Select	c.2046G>C	p.Arg682Arg	synonymous	Exon 9 of 12	NP_056219.3	Q9P202-1
	WHRN	NM_001173425.2		c.2046G>C	p.Arg682Arg	synonymous	Exon 9 of 12	NP_001166896.1
	WHRN	NM_001346890.1		c.993G>C	p.Arg331Arg	synonymous	Exon 5 of 8	NP_001333819.1	Q9P202-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	ENST00000362057.4	TSL:1 MANE Select	c.2046G>C	p.Arg682Arg	synonymous	Exon 9 of 12	ENSP00000354623.3	Q9P202-1
	WHRN	ENST00000265134.10	TSL:1	c.897G>C	p.Arg299Arg	synonymous	Exon 9 of 12	ENSP00000265134.6	Q9P202-3
	WHRN	ENST00000866780.1		c.2046G>C	p.Arg682Arg	synonymous	Exon 9 of 12	ENSP00000536839.1

Frequencies

GnomAD3 genomes AF: 0.00509 AC: 775 AN: 152134 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00131 AC: 326 AN: 249428 AF XY: 0.000890

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.000984

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000548 AC: 801 AN: 1460640 Hom.: 5 Cov.: 33 AF XY: 0.000468 AC XY: 340 AN XY: 726412

African (AFR) AF: 0.0184 AC: 617 AN: 33450

American (AMR) AF: 0.000940 AC: 42 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53180

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0000549 AC: 61 AN: 1111246

Other (OTH) AF: 0.00121 AC: 73 AN: 60338

GnomAD4 genome AF: 0.00509 AC: 775 AN: 152252 Hom.: 9 Cov.: 33 AF XY: 0.00480 AC XY: 357 AN XY: 74448

African (AFR) AF: 0.0173 AC: 719 AN: 41552

American (AMR) AF: 0.00288 AC: 44 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68012

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00126 Hom.: 0

Bravo AF: 0.00567

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.7
DANN	Benign	0.49
PhyloP100		0.035
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs35258467;

hg19: chr9-117168825;