rs1553168601
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_004700.4(KCNQ4):c.1667_1671dup(p.Val558ThrfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y556Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Consequence
KCNQ4
NM_004700.4 frameshift
NM_004700.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.32
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 Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-40835019-T-TACGAC is Pathogenic according to our data. Variant chr1-40835019-T-TACGAC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505873.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ4 | NM_004700.4 | c.1667_1671dup | p.Val558ThrfsTer3 | frameshift_variant | 12/14 | ENST00000347132.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ4 | ENST00000347132.10 | c.1667_1671dup | p.Val558ThrfsTer3 | frameshift_variant | 12/14 | 1 | NM_004700.4 | P2 | |
KCNQ4 | ENST00000443478.3 | c.1248_1252dup | p.Val419ThrfsTer3 | frameshift_variant | 11/13 | 5 | |||
KCNQ4 | ENST00000509682.6 | c.1505_1509dup | p.Val504ThrfsTer3 | frameshift_variant | 11/13 | 5 | A1 | ||
KCNQ4 | ENST00000506017.1 | n.986_990dup | non_coding_transcript_exon_variant | 9/11 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 09, 2017 | The p.Val558ThrfsX3 (NM_004700.3 c.1671_1672insACGAC) variant in KCNQ4 has not b een previously reported in individuals with hearing loss and is absent from larg e population studies. This variant is predicted to cause a frameshift, which alt ers the protein?s amino acid sequence beginning at position 558 and leads to a p remature termination codon 3 amino acids downstream. This alteration is then pre dicted to lead to a truncated or absent protein. Heterozygous loss of function o f the KCNQ4 gene is an established disease mechanism in hearing loss. In summary , although additional studies are required to fully establish its clinical signi ficance, the p.Val558ThrfsX3 variant is likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at