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GeneBe

1-40819423-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_004700.4(KCNQ4):c.785A>T(p.Asp262Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D262G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

KCNQ4
NM_004700.4 missense

Scores

7
5
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.46
Variant links:
Genes affected
KCNQ4 (HGNC:6298): (potassium voltage-gated channel subfamily Q member 4) The protein encoded by this gene forms a potassium channel that is thought to play a critical role in the regulation of neuronal excitability, particularly in sensory cells of the cochlea. The current generated by this channel is inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. The encoded protein can form a homomultimeric potassium channel or possibly a heteromultimeric channel in association with the protein encoded by the KCNQ3 gene. Defects in this gene are a cause of nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004700.4
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 1-40819423-A-T is Pathogenic according to our data. Variant chr1-40819423-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 21427.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40819423-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNQ4NM_004700.4 linkuse as main transcriptc.785A>T p.Asp262Val missense_variant 5/14 ENST00000347132.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNQ4ENST00000347132.10 linkuse as main transcriptc.785A>T p.Asp262Val missense_variant 5/141 NM_004700.4 P2P56696-1
KCNQ4ENST00000509682.6 linkuse as main transcriptc.785A>T p.Asp262Val missense_variant 5/135 A1P56696-2
KCNQ4ENST00000443478.3 linkuse as main transcriptc.473A>T p.Asp158Val missense_variant 4/135
KCNQ4ENST00000506017.1 linkuse as main transcriptn.104A>T non_coding_transcript_exon_variant 2/112

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461714
Hom.:
0
Cov.:
36
AF XY:
0.00
AC XY:
0
AN XY:
727170
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 2A Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyClinVar Staff, National Center for Biotechnology Information (NCBI)Aug 20, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.55
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.50
Cadd
Pathogenic
34
Dann
Uncertain
0.99
DEOGEN2
Pathogenic
0.91
D;D;.
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Pathogenic
0.59
D
MetaRNN
Pathogenic
0.96
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.7
L;L;L
MutationTaster
Benign
1.0
A;A
PrimateAI
Pathogenic
0.81
D
Polyphen
1.0
D;D;P
Vest4
0.93, 0.81
MutPred
0.82
Loss of disorder (P = 0.0078);Loss of disorder (P = 0.0078);Loss of disorder (P = 0.0078);
MVP
1.0
MPC
2.6
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.87
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.51
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.51
Position offset: -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: rs80358275; hg19: chr1-41285095; API