chr9-114426434-T-C

Variant names:

• chr9-114426434-T-C
• rs2274163
• NM_015404.4:c.964-21A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015404.4(WHRN):​c.964-21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,612,952 control chromosomes in the GnomAD database, including 74,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7470 hom., cov: 33)
  • Exomes 𝑓: 0.30 (67272 hom.)
• Consequence: WHRN NM_015404.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.643
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-114426434-T-C is Benign according to our data. Variant chr9-114426434-T-C is described in ClinVar as Benign. ClinVar VariationId is 1238923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.362 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.964-21A>G		intron	N/A	NP_056219.3	Q9P202-1
	WHRN	NM_001173425.2		c.964-21A>G		intron	N/A	NP_001166896.1
	WHRN	NM_001083885.3		c.-186-21A>G		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.964-21A>G		intron	N/A	ENSP00000354623.3	Q9P202-1
	WHRN	ENST00000265134.10	TSL:1	c.-186-21A>G		intron	N/A	ENSP00000265134.6	Q9P202-3
	WHRN	ENST00000866780.1		c.964-21A>G		intron	N/A	ENSP00000536839.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47540 AN: 151868 Hom.: 7449 Cov.: 33

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.320

GnomAD2 exomes AF: 0.330 AC: 81254 AN: 246114 AF XY: 0.323

Gnomad AFR exome AF: 0.331

Gnomad AMR exome AF: 0.468

Gnomad ASJ exome AF: 0.282

Gnomad EAS exome AF: 0.384

Gnomad FIN exome AF: 0.287

Gnomad NFE exome AF: 0.286

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.300 AC: 438246 AN: 1460966 Hom.: 67272 Cov.: 33 AF XY: 0.300 AC XY: 218253 AN XY: 726756

African (AFR) AF: 0.332 AC: 11117 AN: 33472

American (AMR) AF: 0.457 AC: 20423 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 7428 AN: 26136

East Asian (EAS) AF: 0.401 AC: 15918 AN: 39696

South Asian (SAS) AF: 0.352 AC: 30388 AN: 86224

European-Finnish (FIN) AF: 0.286 AC: 15156 AN: 53018

Middle Eastern (MID) AF: 0.290 AC: 1648 AN: 5686

European-Non Finnish (NFE) AF: 0.286 AC: 317823 AN: 1111658

Other (OTH) AF: 0.304 AC: 18345 AN: 60366

GnomAD4 genome AF: 0.313 AC: 47611 AN: 151986 Hom.: 7470 Cov.: 33 AF XY: 0.313 AC XY: 23281 AN XY: 74300

African (AFR) AF: 0.333 AC: 13805 AN: 41432

American (AMR) AF: 0.370 AC: 5658 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1048 AN: 3468

East Asian (EAS) AF: 0.374 AC: 1929 AN: 5162

South Asian (SAS) AF: 0.346 AC: 1671 AN: 4824

European-Finnish (FIN) AF: 0.290 AC: 3063 AN: 10574

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

European-Non Finnish (NFE) AF: 0.286 AC: 19433 AN: 67934

Other (OTH) AF: 0.317 AC: 669 AN: 2110

Alfa AF: 0.307 Hom.: 4143

Bravo AF: 0.323

Asia WGS AF: 0.332 AC: 1155 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 31 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.8
DANN	Benign	0.76
PhyloP100		-0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2274163; hg19: chr9-117188714; COSMIC: COSV54328529; COSMIC: COSV54328529;