rs186194682
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2
The NM_001378969.1(KCND3):c.1769G>A(p.Arg590His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001378969.1 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCND3 | NM_001378969.1 | c.1769G>A | p.Arg590His | missense_variant, splice_region_variant | 8/8 | ENST00000302127.5 | NP_001365898.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCND3 | ENST00000302127.5 | c.1769G>A | p.Arg590His | missense_variant, splice_region_variant | 8/8 | 5 | NM_001378969.1 | ENSP00000306923.4 | ||
KCND3 | ENST00000315987.6 | c.1769G>A | p.Arg590His | missense_variant, splice_region_variant | 8/8 | 1 | ENSP00000319591.2 | |||
KCND3 | ENST00000369697.5 | c.1712G>A | p.Arg571His | missense_variant, splice_region_variant | 6/6 | 1 | ENSP00000358711.1 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152076Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000562 AC: 14AN: 249234Hom.: 0 AF XY: 0.0000668 AC XY: 9AN XY: 134740
GnomAD4 exome AF: 0.0000370 AC: 54AN: 1461372Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33AN XY: 726932
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74406
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 07, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2024 | In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Spinocerebellar ataxia type 19/22 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 28, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 586063). This variant has not been reported in the literature in individuals affected with KCND3-related conditions. This variant is present in population databases (rs186194682, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 590 of the KCND3 protein (p.Arg590His). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 07, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at