rs1408528

Variant names:

• chr9-114458493-C-T
• rs1408528
• NM_015404.4:c.963+7774G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015404.4(WHRN):​c.963+7774G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.746 in 152,124 control chromosomes in the GnomAD database, including 42,535 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.75 (42535 hom., cov: 32)
• Consequence: WHRN NM_015404.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• Publications: 6 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, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• autosomal recessive nonsyndromic hearing loss 31

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.943 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.963+7774G>A		intron	N/A	NP_056219.3	Q9P202-1
	WHRN	NM_001173425.2		c.963+7774G>A		intron	N/A	NP_001166896.1
	WHRN	NM_001083885.3		c.-187+7774G>A		intron	N/A	NP_001077354.2	Q9P202-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	ENST00000362057.4	TSL:1 MANE Select	c.963+7774G>A		intron	N/A	ENSP00000354623.3	Q9P202-1
	WHRN	ENST00000265134.10	TSL:1	c.-187+7774G>A		intron	N/A	ENSP00000265134.6	Q9P202-3
	WHRN	ENST00000866780.1		c.963+7774G>A		intron	N/A	ENSP00000536839.1

Frequencies

GnomAD3 genomes AF: 0.746 AC: 113409 AN: 152006 Hom.: 42496 Cov.: 32

Gnomad AFR AF: 0.710

Gnomad AMI AF: 0.826

Gnomad AMR AF: 0.796

Gnomad ASJ AF: 0.698

Gnomad EAS AF: 0.965

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.689

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.745

Gnomad OTH AF: 0.739

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.746 AC: 113500 AN: 152124 Hom.: 42535 Cov.: 32 AF XY: 0.746 AC XY: 55451 AN XY: 74364

African (AFR) AF: 0.709 AC: 29414 AN: 41472

American (AMR) AF: 0.796 AC: 12168 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.698 AC: 2423 AN: 3470

East Asian (EAS) AF: 0.965 AC: 5000 AN: 5180

South Asian (SAS) AF: 0.832 AC: 4015 AN: 4828

European-Finnish (FIN) AF: 0.689 AC: 7297 AN: 10592

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.745 AC: 50669 AN: 67990

Other (OTH) AF: 0.742 AC: 1565 AN: 2110

Alfa AF: 0.744 Hom.: 21371

Bravo AF: 0.753

Asia WGS AF: 0.868 AC: 3017 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.14
DANN	Benign	0.72
PhyloP100		-1.3
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: rs1408528; hg19: chr9-117220773; COSMIC: COSV54328843;