rs765435145

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_020697.4(KCNS2):​c.1088C>A​(p.Ala363Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A363V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

KCNS2
NM_020697.4 missense

Scores

8
7
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91
Variant links:
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNS2NM_020697.4 linkc.1088C>A p.Ala363Asp missense_variant Exon 2 of 2 ENST00000287042.5 NP_065748.1 Q9ULS6
STK3XM_047422133.1 linkc.1423+8036G>T intron_variant Intron 11 of 11 XP_047278089.1
STK3XR_007060752.1 linkn.1571+8036G>T intron_variant Intron 11 of 14
STK3XR_007060753.1 linkn.1571+8036G>T intron_variant Intron 11 of 12

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNS2ENST00000287042.5 linkc.1088C>A p.Ala363Asp missense_variant Exon 2 of 2 1 NM_020697.4 ENSP00000287042.4 Q9ULS6
KCNS2ENST00000521839.1 linkc.1088C>A p.Ala363Asp missense_variant Exon 2 of 2 5 ENSP00000430712.1 Q9ULS6
STK3ENST00000517832.1 linkn.483+5060G>T intron_variant Intron 3 of 3 3
STK3ENST00000649151.1 linkn.427+5060G>T intron_variant Intron 3 of 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251154
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135732
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1460788
Hom.:
0
Cov.:
32
AF XY:
0.00000551
AC XY:
4
AN XY:
726502
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.54
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.76
D;D
Eigen
Uncertain
0.62
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.66
.;T
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Pathogenic
0.88
D
MutationAssessor
Benign
1.2
L;L
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-3.0
D;D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.014
D;D
Sift4G
Benign
0.37
T;T
Polyphen
0.99
D;D
Vest4
0.78
MutPred
0.64
Loss of glycosylation at T360 (P = 0.1336);Loss of glycosylation at T360 (P = 0.1336);
MVP
0.98
MPC
1.9
ClinPred
0.94
D
GERP RS
6.1
Varity_R
0.44
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs765435145; hg19: chr8-99441295; API