8-98428362-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020697.4(KCNS2):c.383T>C(p.Val128Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000121 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

KCNS2
NM_020697.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.00

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.035281718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KCNS2	NM_020697.4 linkuse as main transcript	c.383T>C	p.Val128Ala	missense_variant	2/2	ENST00000287042.5
STK3	XM_047422133.1 linkuse as main transcript	c.1423+8741A>G		intron_variant
STK3	XR_007060752.1 linkuse as main transcript	n.1571+8741A>G		intron_variant, non_coding_transcript_variant
STK3	XR_007060753.1 linkuse as main transcript	n.1571+8741A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
KCNS2	ENST00000287042.5 linkuse as main transcript	c.383T>C	p.Val128Ala	missense_variant	2/2	1	NM_020697.4	P1
KCNS2	ENST00000521839.1 linkuse as main transcript	c.383T>C	p.Val128Ala	missense_variant	2/2	5		P1
STK3	ENST00000517832.1 linkuse as main transcript	n.483+5765A>G		intron_variant, non_coding_transcript_variant		3
STK3	ENST00000649151.1 linkuse as main transcript	n.427+5765A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251400

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

182

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000693

Gnomad4 NFE exome

AF:

0.000123

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.0000883

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.0000767

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

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 24, 2022

The c.383T>C (p.V128A) alteration is located in exon 2 (coding exon 1) of the KCNS2 gene. This alteration results from a T to C substitution at nucleotide position 383, causing the valine (V) at amino acid position 128 to be replaced by an alanine (A). 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

0.10

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.56

Cadd

Benign

Dann

Benign

0.78

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

0.012

FATHMM_MKL

Benign

0.47

M_CAP

Benign

0.0037

MetaRNN

Benign

0.035

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

0.72

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.14

N;N

REVEL

Benign

0.086

Sift

Benign

0.29

T;T

Sift4G

Benign

0.72

T;T

Polyphen

0.0

B;B

Vest4

0.11

MVP

0.26

MPC

0.71

ClinPred

0.029

GERP RS

4.2

Varity_R

0.062

gMVP

0.36

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