rs137896524
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_004700.4(KCNQ4):c.972G>A(p.Leu324=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,610,128 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0021 ( 40 hom. )
Consequence
KCNQ4
NM_004700.4 synonymous
NM_004700.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.07
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 -16 ACMG points.
BP6
?
Variant 1-40820191-G-A is Benign according to our data. Variant chr1-40820191-G-A is described in ClinVar as [Benign]. Clinvar id is 163750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40820191-G-A is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00142 (216/152336) while in subpopulation SAS AF= 0.0188 (91/4828). AF 95% confidence interval is 0.0157. There are 1 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 216 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ4 | NM_004700.4 | c.972G>A | p.Leu324= | synonymous_variant | 7/14 | ENST00000347132.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ4 | ENST00000347132.10 | c.972G>A | p.Leu324= | synonymous_variant | 7/14 | 1 | NM_004700.4 | P2 | |
KCNQ4 | ENST00000509682.6 | c.972G>A | p.Leu324= | synonymous_variant | 7/13 | 5 | A1 | ||
KCNQ4 | ENST00000443478.3 | c.660G>A | p.Leu220= | synonymous_variant | 6/13 | 5 | |||
KCNQ4 | ENST00000506017.1 | n.291G>A | non_coding_transcript_exon_variant | 4/11 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00142 AC: 216AN: 152218Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00320 AC: 774AN: 242222Hom.: 9 AF XY: 0.00420 AC XY: 551AN XY: 131202
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GnomAD4 exome AF: 0.00209 AC: 3045AN: 1457792Hom.: 40 Cov.: 32 AF XY: 0.00273 AC XY: 1981AN XY: 724900
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GnomAD4 genome ? AF: 0.00142 AC: 216AN: 152336Hom.: 1 Cov.: 33 AF XY: 0.00152 AC XY: 113AN XY: 74496
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 02, 2015 | p.Leu324Leu in exon 7 of KCNQ4: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 2.4% (297/12304) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs137896524). - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Autosomal dominant nonsyndromic hearing loss 2A Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 16, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 29, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at