rs55964611
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_004700.4(KCNQ4):c.1665G>A(p.Pro555=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0366 in 1,613,944 control chromosomes in the GnomAD database, including 1,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.032 ( 122 hom., cov: 31)
Exomes 𝑓: 0.037 ( 1111 hom. )
Consequence
KCNQ4
NM_004700.4 synonymous
NM_004700.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -5.63
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 -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant 1-40835018-G-A is Benign according to our data. Variant chr1-40835018-G-A is described in ClinVar as [Benign]. Clinvar id is 45103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40835018-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-5.63 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0315 (4805/152320) while in subpopulation NFE AF= 0.0453 (3081/68026). AF 95% confidence interval is 0.044. There are 122 homozygotes in gnomad4. There are 2309 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 4805 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ4 | NM_004700.4 | c.1665G>A | p.Pro555= | synonymous_variant | 12/14 | ENST00000347132.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ4 | ENST00000347132.10 | c.1665G>A | p.Pro555= | synonymous_variant | 12/14 | 1 | NM_004700.4 | P2 | |
KCNQ4 | ENST00000509682.6 | c.1503G>A | p.Pro501= | synonymous_variant | 11/13 | 5 | A1 | ||
KCNQ4 | ENST00000443478.3 | c.1248G>A | p.Pro416= | synonymous_variant | 11/13 | 5 | |||
KCNQ4 | ENST00000506017.1 | n.984G>A | non_coding_transcript_exon_variant | 9/11 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0315 AC: 4801AN: 152202Hom.: 121 Cov.: 31
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GnomAD3 exomes AF: 0.0301 AC: 7569AN: 251452Hom.: 181 AF XY: 0.0304 AC XY: 4131AN XY: 135916
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GnomAD4 exome AF: 0.0371 AC: 54282AN: 1461624Hom.: 1111 Cov.: 31 AF XY: 0.0364 AC XY: 26464AN XY: 727118
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GnomAD4 genome AF: 0.0315 AC: 4805AN: 152320Hom.: 122 Cov.: 31 AF XY: 0.0310 AC XY: 2309AN XY: 74480
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ClinVar
Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 07, 2012 | Pro555Pro in Exon 12 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 3.9% (276/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs55964611). - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 09, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | - - |
Autosomal dominant nonsyndromic hearing loss 2A Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Computational scores
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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
Find out detailed SpliceAI scores and Pangolin per-transcript scores at