8-98429029-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020697.4(KCNS2):c.1050T>G(p.Ile350Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,476 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 1 hom. )

Consequence

KCNS2
NM_020697.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.403

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]

KCNS2 links:

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]

STK3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40928072).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNS2	NM_020697.4 link	c.1050T>G	p.Ile350Met	missense_variant	Exon 2 of 2	ENST00000287042.5	NP_065748.1	Q9ULS6
STK3	XM_047422133.1 link	c.1423+8074A>C		intron_variant	Intron 11 of 11		XP_047278089.1
STK3	XR_007060752.1 link	n.1571+8074A>C		intron_variant	Intron 11 of 14
STK3	XR_007060753.1 link	n.1571+8074A>C		intron_variant	Intron 11 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNS2	ENST00000287042.5 link	c.1050T>G	p.Ile350Met	missense_variant	Exon 2 of 2	1	NM_020697.4	ENSP00000287042.4	Q9ULS6
KCNS2	ENST00000521839.1 link	c.1050T>G	p.Ile350Met	missense_variant	Exon 2 of 2	5		ENSP00000430712.1	Q9ULS6
STK3	ENST00000517832.1 link	n.483+5098A>C		intron_variant	Intron 3 of 3	3
STK3	ENST00000649151.1 link	n.427+5098A>C		intron_variant	Intron 3 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251154

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461476

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726964

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1050T>G (p.I350M) alteration is located in exon 2 (coding exon 1) of the KCNS2 gene. This alteration results from a T to G substitution at nucleotide position 1050, causing the isoleucine (I) at amino acid position 350 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

0.0053

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

3.7

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

D;D

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.83

.;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.41

T;T

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

0.98

L;L

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.36

N;N

REVEL

Uncertain

0.56

Sift

Uncertain

0.0040

D;D

Sift4G

Benign

0.25

T;T

Polyphen

0.83

P;P

Vest4

0.43

MutPred

0.47

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MVP

0.72

MPC

1.3

ClinPred

0.51

GERP RS

-3.8

Varity_R

0.24

gMVP

0.72

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over