8-98428598-A-C

Position:

• chr8-98428598-A-C

Variant summary

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

The NM_020697.4(KCNS2):​c.619A>C​(p.Asn207His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNS2 NM_020697.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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]

STK3 (HGNC:):

ACMG classification

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	Protein	UniProt
KCNS2	NM_020697.4	c.619A>C	p.Asn207His	missense_variant	2/2	ENST00000287042.5	NP_065748.1
STK3	XM_047422133.1	c.1423+8505T>G		intron_variant			XP_047278089.1
STK3	XR_007060752.1	n.1571+8505T>G		intron_variant
STK3	XR_007060753.1	n.1571+8505T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNS2	ENST00000287042.5	c.619A>C	p.Asn207His	missense_variant	2/2	1	NM_020697.4	ENSP00000287042.4
KCNS2	ENST00000521839.1	c.619A>C	p.Asn207His	missense_variant	2/2	5		ENSP00000430712.1
STK3	ENST00000517832.1	n.483+5529T>G		intron_variant		3
STK3	ENST00000649151.1	n.427+5529T>G		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2024

The c.619A>C (p.N207H) alteration is located in exon 2 (coding exon 1) of the KCNS2 gene. This alteration results from a A to C substitution at nucleotide position 619, causing the asparagine (N) at amino acid position 207 to be replaced by a histidine (H). 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	0.12
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Benign	0.85
DEOGEN2	Uncertain	0.79	D;D
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	.;T
M_CAP	Uncertain	0.090	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	0.99	L;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.92	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.62	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.33	B;B
Vest4		0.78
MutPred		0.50		Gain of catalytic residue at N207 (P = 0.0373);Gain of catalytic residue at N207 (P = 0.0373);
MVP		0.86
MPC		1.6
ClinPred		0.69	D
GERP RS		5.8
Varity_R		0.24
gMVP		0.87

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.

Other links and lift over

hg19: chr8-99440826;