9-114478750-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015404.4(WHRN):​c.640C>G​(p.Leu214Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

WHRN
NM_015404.4 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.48
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23357159).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
WHRNNM_015404.4 linkuse as main transcriptc.640C>G p.Leu214Val missense_variant 2/12 ENST00000362057.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
WHRNENST00000362057.4 linkuse as main transcriptc.640C>G p.Leu214Val missense_variant 2/121 NM_015404.4 P1Q9P202-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 18, 2017The p.Leu214Val variant in DFNB31 has not been previously reported in individual s with hearing loss and was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p .Leu214Val variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.51
BayesDel_addAF
Benign
-0.0041
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.12
T;.
Eigen
Benign
0.081
Eigen_PC
Benign
0.18
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.23
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L;L
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-1.9
N;N
REVEL
Benign
0.15
Sift
Benign
0.13
T;T
Sift4G
Uncertain
0.0080
D;D
Polyphen
0.58
P;D
Vest4
0.39
MutPred
0.45
Gain of glycosylation at S211 (P = 0.0825);Gain of glycosylation at S211 (P = 0.0825);
MVP
0.37
MPC
1.1
ClinPred
0.94
D
GERP RS
3.8
Varity_R
0.36
gMVP
0.29

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554735418; hg19: chr9-117241030; API