8-98428008-C-T

Variant names:

• chr8-98428008-C-T
• rs777451821
• NM_020697.4:c.29C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020697.4(KCNS2):​c.29C>T​(p.Ser10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,430,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. S10W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KCNS2 NM_020697.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19846591).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020697.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNS2	NM_020697.4	MANE Select	c.29C>T	p.Ser10Leu	missense	Exon 2 of 2	NP_065748.1	Q9ULS6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNS2	ENST00000287042.5	TSL:1 MANE Select	c.29C>T	p.Ser10Leu	missense	Exon 2 of 2	ENSP00000287042.4	Q9ULS6
	KCNS2	ENST00000521839.1	TSL:5	c.29C>T	p.Ser10Leu	missense	Exon 2 of 2	ENSP00000430712.1	Q9ULS6
	STK3	ENST00000517832.1	TSL:3	n.483+6119G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1430148 Hom.: 0 Cov.: 32 AF XY: 0.00000424 AC XY: 3 AN XY: 707846

African (AFR) AF: 0.00 AC: 0 AN: 32724

American (AMR) AF: 0.00 AC: 0 AN: 40494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25236

East Asian (EAS) AF: 0.00 AC: 0 AN: 37850

South Asian (SAS) AF: 0.00 AC: 0 AN: 82642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1095012

Other (OTH) AF: 0.00 AC: 0 AN: 59042

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.069	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.0	L
PhyloP100		2.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.99	N
REVEL	Benign	0.25
Sift	Benign	0.093	T
Sift4G	Benign	0.14	T
Polyphen		0.41	B
Vest4		0.22
MutPred		0.45		Loss of disorder (P = 0.0376)
MVP		0.55
MPC		0.52
ClinPred		0.43	T
GERP RS		3.9
PromoterAI		-0.0060	Neutral
Varity_R		0.082
gMVP		0.51
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs777451821; hg19: chr8-99440236;