chr8-98429261-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_020697.4(KCNS2):c.1282C>T(p.Arg428Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 0 hom. )
Consequence
KCNS2
NM_020697.4 missense
NM_020697.4 missense
Scores
4
8
6
Clinical Significance
Conservation
PhyloP100: 2.94
Genes affected
KCNS2 (HGNC:6301): (potassium voltage-gated channel modifier subfamily S member 2) Predicted to enable voltage-gated potassium channel activity. Predicted to be involved in potassium ion transmembrane transport and regulation of delayed rectifier potassium channel activity. Predicted to be located in perinuclear region of cytoplasm and plasma membrane. Predicted to be part of voltage-gated potassium channel complex. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]
STK3 (HGNC:11406): (serine/threonine kinase 3) This gene encodes a serine/threonine protein kinase activated by proapoptotic molecules indicating the encoded protein functions as a growth suppressor. Cleavage of the protein product by caspase removes the inhibitory C-terminal portion. The N-terminal portion is transported to the nucleus where it homodimerizes to form the active kinase which promotes the condensation of chromatin during apoptosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNS2 | NM_020697.4 | c.1282C>T | p.Arg428Cys | missense_variant | 2/2 | ENST00000287042.5 | |
STK3 | XM_047422133.1 | c.1423+7842G>A | intron_variant | ||||
STK3 | XR_007060752.1 | n.1571+7842G>A | intron_variant, non_coding_transcript_variant | ||||
STK3 | XR_007060753.1 | n.1571+7842G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNS2 | ENST00000287042.5 | c.1282C>T | p.Arg428Cys | missense_variant | 2/2 | 1 | NM_020697.4 | P1 | |
KCNS2 | ENST00000521839.1 | c.1282C>T | p.Arg428Cys | missense_variant | 2/2 | 5 | P1 | ||
STK3 | ENST00000517832.1 | n.483+4866G>A | intron_variant, non_coding_transcript_variant | 3 | |||||
STK3 | ENST00000649151.1 | n.427+4866G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152230Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250402Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135364
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GnomAD4 exome AF: 0.0000493 AC: 72AN: 1461732Hom.: 0 Cov.: 32 AF XY: 0.0000495 AC XY: 36AN XY: 727156
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GnomAD4 genome AF: 0.0000328 AC: 5AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74368
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 11, 2022 | The c.1282C>T (p.R428C) alteration is located in exon 2 (coding exon 1) of the KCNS2 gene. This alteration results from a C to T substitution at nucleotide position 1282, causing the arginine (R) at amino acid position 428 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
DEOGEN2
Uncertain
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
D;D
Vest4
MutPred
Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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