rs727503105
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Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2
The NM_004700.4(KCNQ4):c.1263G>A(p.Pro421=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000398 in 1,607,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000038 ( 0 hom. )
Consequence
KCNQ4
NM_004700.4 synonymous
NM_004700.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.00400
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 Benign. Variant got -15 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
?
Variant 1-40824229-G-A is Benign according to our data. Variant chr1-40824229-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 163752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40824229-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-0.004 with no splicing effect.
BS2
?
High AC in GnomAd4 at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ4 | NM_004700.4 | c.1263G>A | p.Pro421= | synonymous_variant | 9/14 | ENST00000347132.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ4 | ENST00000347132.10 | c.1263G>A | p.Pro421= | synonymous_variant | 9/14 | 1 | NM_004700.4 | P2 | |
KCNQ4 | ENST00000443478.3 | c.816+1827G>A | intron_variant | 5 | |||||
KCNQ4 | ENST00000509682.6 | c.1130+1827G>A | intron_variant | 5 | A1 | ||||
KCNQ4 | ENST00000506017.1 | n.582G>A | non_coding_transcript_exon_variant | 6/11 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152180Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000220 AC: 5AN: 227278Hom.: 0 AF XY: 0.0000398 AC XY: 5AN XY: 125496
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GnomAD4 exome AF: 0.0000385 AC: 56AN: 1455812Hom.: 0 Cov.: 33 AF XY: 0.0000428 AC XY: 31AN XY: 723882
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152180Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74338
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 05, 2013 | Pro421Pro in Exon 09 of KCNQ4: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at