rs6478078

Variant names:

• chr9-114404058-C-G
• rs6478078
• NM_015404.4:c.2256G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-114404058-C-G
• chr9-114404058-C-A
• chr9-114404058-C-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_015404.4(WHRN):​c.2256G>C​(p.Gln752His) variant causes a missense change. The variant allele was found at a frequency of 0.000932 in 1,613,212 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (6 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.45
• Publications: 30 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.093723685).
• BP6: Variant 9-114404058-C-G is Benign according to our data. Variant chr9-114404058-C-G is described in ClinVar as Benign. ClinVar VariationId is 177749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00524 (798/152360) while in subpopulation AFR AF = 0.0185 (771/41594). AF 95% confidence interval is 0.0175. There are 5 homozygotes in GnomAd4. There are 371 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR 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.2256G>C	p.Gln752His	missense	Exon 10 of 12	NP_056219.3	Q9P202-1
	WHRN	NM_001173425.2		c.2253G>C	p.Gln751His	missense	Exon 10 of 12	NP_001166896.1
	WHRN	NM_001346890.1		c.1203G>C	p.Gln401His	missense	Exon 6 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.2256G>C	p.Gln752His	missense	Exon 10 of 12	ENSP00000354623.3	Q9P202-1
	WHRN	ENST00000265134.10	TSL:1	c.1107G>C	p.Gln369His	missense	Exon 10 of 12	ENSP00000265134.6	Q9P202-3
	WHRN	ENST00000866780.1		c.2253G>C	p.Gln751His	missense	Exon 10 of 12	ENSP00000536839.1

Frequencies

GnomAD3 genomes AF: 0.00523 AC: 796 AN: 152242 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000483 AC: 706 AN: 1460852 Hom.: 6 Cov.: 35 AF XY: 0.000438 AC XY: 318 AN XY: 726678

African (AFR) AF: 0.0165 AC: 554 AN: 33480

American (AMR) AF: 0.00121 AC: 54 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52408

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111988

Other (OTH) AF: 0.00116 AC: 70 AN: 60392

GnomAD4 genome AF: 0.00524 AC: 798 AN: 152360 Hom.: 5 Cov.: 33 AF XY: 0.00498 AC XY: 371 AN XY: 74516

African (AFR) AF: 0.0185 AC: 771 AN: 41594

American (AMR) AF: 0.00124 AC: 19 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.0170 Hom.: 784

Bravo AF: 0.00571

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_noAF	Benign	-0.59
CADD	Pathogenic	26
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.094	T
PhyloP100		5.5
Sift4G	Uncertain	0.0070	D
Vest4		0.68
gMVP		0.64

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6478078; hg19: chr9-117166338;