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
NM_004700.4 missense
Scores
7
5
2
Clinical Significance
Conservation
PhyloP100: 4.46
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 |
---|---|---|---|---|---|---|---|
KCNQ4 | NM_004700.4 | c.785A>T | p.Asp262Val | missense_variant | 5/14 | ENST00000347132.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ4 | ENST00000347132.10 | c.785A>T | p.Asp262Val | missense_variant | 5/14 | 1 | NM_004700.4 | P2 | |
KCNQ4 | ENST00000509682.6 | c.785A>T | p.Asp262Val | missense_variant | 5/13 | 5 | A1 | ||
KCNQ4 | ENST00000443478.3 | c.473A>T | p.Asp158Val | missense_variant | 4/13 | 5 | |||
KCNQ4 | ENST00000506017.1 | n.104A>T | non_coding_transcript_exon_variant | 2/11 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461714Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 727170
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1461714
Hom.:
Cov.:
36
AF XY:
AC XY:
0
AN XY:
727170
Gnomad4 AFR exome
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Gnomad4 AMR exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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Gnomad4 OTH exome
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GnomAD4 genome ? Cov.: 32
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 provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | Aug 20, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;L;L
MutationTaster
Benign
A;A
PrimateAI
Pathogenic
D
Polyphen
D;D;P
Vest4
0.93, 0.81
MutPred
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
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at