rs117352600

Variant names:

• chr9-114424398-C-T
• rs117352600
• NM_015404.4:c.1352G>A
• WHRN p.Gly451Asp

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015404.4(WHRN):​c.1352G>A​(p.Gly451Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,612,848 control chromosomes in the GnomAD database, including 56 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 Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G451R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (51 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.92
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028752685).
• BP6: Variant 9-114424398-C-T is Benign according to our data. Variant chr9-114424398-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00165 (251/152342) while in subpopulation EAS AF = 0.0404 (209/5172). AF 95% confidence interval is 0.0359. There are 5 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.1352G>A	p.Gly451Asp	missense	Exon 6 of 12	NP_056219.3	Q9P202-1
	WHRN	NM_001173425.2		c.1352G>A	p.Gly451Asp	missense	Exon 6 of 12	NP_001166896.1
	WHRN	NM_001346890.1		c.299G>A	p.Gly100Asp	missense	Exon 2 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.1352G>A	p.Gly451Asp	missense	Exon 6 of 12	ENSP00000354623.3	Q9P202-1
	WHRN	ENST00000265134.10	TSL:1	c.203G>A	p.Gly68Asp	missense	Exon 6 of 12	ENSP00000265134.6	Q9P202-3
	WHRN	ENST00000866780.1		c.1352G>A	p.Gly451Asp	missense	Exon 6 of 12	ENSP00000536839.1

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 253 AN: 152224 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0405

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00331 AC: 833 AN: 251380 AF XY: 0.00322

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0420

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00136 AC: 1992 AN: 1460506 Hom.: 51 Cov.: 57 AF XY: 0.00136 AC XY: 988 AN XY: 726572

African (AFR) AF: 0.000120 AC: 4 AN: 33436

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0424 AC: 1682 AN: 39698

South Asian (SAS) AF: 0.00104 AC: 90 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00127 AC: 6 AN: 4718

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1111920

Other (OTH) AF: 0.00222 AC: 134 AN: 60266

GnomAD4 genome AF: 0.00165 AC: 251 AN: 152342 Hom.: 5 Cov.: 33 AF XY: 0.00181 AC XY: 135 AN XY: 74492

African (AFR) AF: 0.000361 AC: 15 AN: 41584

American (AMR) AF: 0.000718 AC: 11 AN: 15310

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

East Asian (EAS) AF: 0.0404 AC: 209 AN: 5172

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00172 Hom.: 13

Bravo AF: 0.00193

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.9
DANN	Benign	0.88
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.9
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.078
Sift	Benign	0.53	T
Sift4G	Benign	0.76	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.098
gMVP		0.22
Mutation Taster		=96/4	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: rs117352600;

hg19: chr9-117186678;

COSMIC: COSV54330443;