9-114408030-C-T

Variant names:

• chr9-114408030-C-T
• rs2274160
• NM_015404.4:c.1627-12G>A

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.1627-12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,585,538 control chromosomes in the GnomAD database, including 43,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4077 hom., cov: 33)
  • Exomes 𝑓: 0.23 (39706 hom.)
• Consequence: WHRN NM_015404.4 intron
• Scores: Splicing: ADA: 0.00002423
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.179
• Publications: 15 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=-0.8).
• BP6: Variant 9-114408030-C-T is Benign according to our data. Variant chr9-114408030-C-T is described in ClinVar as Benign. ClinVar VariationId is 45660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.247 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.1627-12G>A		intron	N/A	NP_056219.3	Q9P202-1
	WHRN	NM_001173425.2		c.1627-12G>A		intron	N/A	NP_001166896.1
	WHRN	NM_001346890.1		c.574-12G>A		intron	N/A	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.1627-12G>A		intron	N/A	ENSP00000354623.3	Q9P202-1
	WHRN	ENST00000265134.10	TSL:1	c.478-12G>A		intron	N/A	ENSP00000265134.6	Q9P202-3
	WHRN	ENST00000866780.1		c.1627-12G>A		intron	N/A	ENSP00000536839.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34495 AN: 151946 Hom.: 4079 Cov.: 33

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.0637

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.229

GnomAD2 exomes AF: 0.199 AC: 41936 AN: 210840 AF XY: 0.200

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.0647

Gnomad FIN exome AF: 0.313

Gnomad NFE exome AF: 0.241

Gnomad OTH exome AF: 0.213

GnomAD4 exome AF: 0.229 AC: 328527 AN: 1433476 Hom.: 39706 Cov.: 32 AF XY: 0.228 AC XY: 161850 AN XY: 711018

African (AFR) AF: 0.206 AC: 6768 AN: 32790

American (AMR) AF: 0.121 AC: 5083 AN: 42042

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 5725 AN: 25596

East Asian (EAS) AF: 0.0473 AC: 1828 AN: 38676

South Asian (SAS) AF: 0.139 AC: 11480 AN: 82884

European-Finnish (FIN) AF: 0.309 AC: 15978 AN: 51670

Middle Eastern (MID) AF: 0.247 AC: 1412 AN: 5728

European-Non Finnish (NFE) AF: 0.244 AC: 267393 AN: 1094768

Other (OTH) AF: 0.217 AC: 12860 AN: 59322

GnomAD4 genome AF: 0.227 AC: 34495 AN: 152062 Hom.: 4077 Cov.: 33 AF XY: 0.228 AC XY: 16980 AN XY: 74316

African (AFR) AF: 0.210 AC: 8688 AN: 41454

American (AMR) AF: 0.183 AC: 2803 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 770 AN: 3470

East Asian (EAS) AF: 0.0632 AC: 328 AN: 5186

South Asian (SAS) AF: 0.137 AC: 662 AN: 4816

European-Finnish (FIN) AF: 0.331 AC: 3497 AN: 10562

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 17005 AN: 67980

Other (OTH) AF: 0.227 AC: 478 AN: 2108

Alfa AF: 0.233 Hom.: 6777

Bravo AF: 0.211

Asia WGS AF: 0.116 AC: 404 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.6
DANN	Benign	0.60
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0060
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: rs2274160; hg19: chr9-117170310; COSMIC: COSV54335246;