1-40822312-AGGCTGCCT-A
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP3PP5
The NM_004700.4(KCNQ4):c.1044_1051del(p.Ala349ProfsTer19) variant causes a splice acceptor, coding sequence 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 Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
KCNQ4
NM_004700.4 splice_acceptor, coding_sequence
NM_004700.4 splice_acceptor, coding_sequence
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 10.0
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.
PVS1
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.042145595 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7, offset of 0 (no position change), new splice context is: cacgtcccccataccaccAGgcg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 1-40822312-AGGCTGCCT-A is Pathogenic according to our data. Variant chr1-40822312-AGGCTGCCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 208372.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40822312-AGGCTGCCT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ4 | NM_004700.4 | c.1044_1051del | p.Ala349ProfsTer19 | splice_acceptor_variant, coding_sequence_variant | 8/14 | ENST00000347132.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ4 | ENST00000347132.10 | c.1044_1051del | p.Ala349ProfsTer19 | splice_acceptor_variant, coding_sequence_variant | 8/14 | 1 | NM_004700.4 | P2 | |
KCNQ4 | ENST00000443478.3 | c.730_737del | p.Ala245ProfsTer19 | splice_acceptor_variant, coding_sequence_variant | 7/13 | 5 | |||
KCNQ4 | ENST00000509682.6 | c.1044_1051del | p.Ala349ProfsTer19 | splice_acceptor_variant, coding_sequence_variant | 8/13 | 5 | A1 | ||
KCNQ4 | ENST00000506017.1 | n.363_370del | splice_acceptor_variant, non_coding_transcript_exon_variant | 5/11 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
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
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at