Genetic Variant KCNS2:p.Pro285Thr (chr8-98428832-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020697.4(KCNS2):c.853C>A(p.Pro285Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KCNS2
NM_020697.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.93

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:

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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 rank	MANE	Protein	UniProt
KCNS2	NM_020697.4 link	c.853C>A	p.Pro285Thr	missense_variant	Exon 2 of 2	ENST00000287042.5	NP_065748.1	Q9ULS6
STK3	XM_047422133.1 link	c.1423+8271G>T		intron_variant	Intron 11 of 11		XP_047278089.1
STK3	XR_007060752.1 link	n.1571+8271G>T		intron_variant	Intron 11 of 14
STK3	XR_007060753.1 link	n.1571+8271G>T		intron_variant	Intron 11 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNS2	ENST00000287042.5 link	c.853C>A	p.Pro285Thr	missense_variant	Exon 2 of 2	1	NM_020697.4	ENSP00000287042.4	Q9ULS6
KCNS2	ENST00000521839.1 link	c.853C>A	p.Pro285Thr	missense_variant	Exon 2 of 2	5		ENSP00000430712.1	Q9ULS6
STK3	ENST00000517832.1 link	n.483+5295G>T		intron_variant	Intron 3 of 3	3
STK3	ENST00000649151.1 link	n.427+5295G>T		intron_variant	Intron 3 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.853C>A (p.P285T) alteration is located in exon 2 (coding exon 1) of the KCNS2 gene. This alteration results from a C to A substitution at nucleotide position 853, causing the proline (P) at amino acid position 285 to be replaced by a threonine (T). 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

0.19

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Uncertain

0.43

T;T

Eigen

Benign

0.012

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.90

.;D

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Uncertain

0.65

MutationAssessor

Benign

-0.42

N;N

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.76

N;N

REVEL

Uncertain

0.46

Sift

Benign

0.50

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.82

P;P

Vest4

0.48

MutPred

0.52

Gain of catalytic residue at P285 (P = 0.0042);Gain of catalytic residue at P285 (P = 0.0042);

MVP

0.77

MPC

1.7

ClinPred

0.57

GERP RS

5.8

Varity_R

0.11

gMVP

0.75

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over