chr1-111776247-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_001378969.1(KCND3):c.1798G>A(p.Gly600Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,613,968 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G600A) has been classified as Uncertain significance.
Frequency
Consequence
NM_001378969.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCND3 | NM_001378969.1 | c.1798G>A | p.Gly600Arg | missense_variant | 8/8 | ENST00000302127.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCND3 | ENST00000302127.5 | c.1798G>A | p.Gly600Arg | missense_variant | 8/8 | 5 | NM_001378969.1 | P3 | |
KCND3 | ENST00000315987.6 | c.1798G>A | p.Gly600Arg | missense_variant | 8/8 | 1 | P3 | ||
KCND3 | ENST00000369697.5 | c.1741G>A | p.Gly581Arg | missense_variant | 6/6 | 1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152120Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000638 AC: 16AN: 250980Hom.: 0 AF XY: 0.0000590 AC XY: 8AN XY: 135662
GnomAD4 exome AF: 0.0000985 AC: 144AN: 1461848Hom.: 0 Cov.: 31 AF XY: 0.0000963 AC XY: 70AN XY: 727228
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74292
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 11, 2019 | Published functional studies suggest a damaging effect as this variant significantly increased peak current density and slowed transient outward current inactivation (Giudicessi et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in at least one individual with Brugada syndrome and sudden unexplained death (Giudicessi et al., 2012); This variant is associated with the following publications: (PMID: 22457051, 30662450, 29053796, 22840528) - |
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | May 16, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 07, 2021 | - - |
Brugada syndrome 9 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2012 | - - |
Spinocerebellar ataxia type 19/22;C4225340:Brugada syndrome 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 30, 2021 | - - |
Spinocerebellar ataxia type 19/22 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 28, 2023 | 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. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 600 of the KCND3 protein (p.Gly600Arg). This variant is present in population databases (rs149344567, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 21349352, 22457051). ClinVar contains an entry for this variant (Variation ID: 192254). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCND3 function (PMID: 21349352, 22457051, 26016905). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 18, 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