rs777451821

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr8-98428008-C-G
• chr8-98428008-C-A
• chr8-98428008-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020697.4(KCNS2):​c.29C>G​(p.Ser10Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,148 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 7.0e-7 (0 hom.)
• Consequence: KCNS2 NM_020697.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41174).

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>G	p.Ser10Trp	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>G	p.Ser10Trp	missense	Exon 2 of 2	ENSP00000287042.4	Q9ULS6
	KCNS2	ENST00000521839.1	TSL:5	c.29C>G	p.Ser10Trp	missense	Exon 2 of 2	ENSP00000430712.1	Q9ULS6
	STK3	ENST00000517832.1	TSL:3	n.483+6119G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000489 AC: 1 AN: 204590 AF XY: 0.00000903

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000113

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430148 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 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: 9.13e-7 AC: 1 AN: 1095012

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

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000830 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.032
Eigen_PC	Benign	-0.031
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	0.49	N
PhyloP100		2.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.010	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.023	D
Polyphen		0.98	D
Vest4		0.42
MutPred		0.51		Loss of disorder (P = 0.0172)
MVP		0.73
MPC		1.1
ClinPred		0.30	T
GERP RS		3.9
PromoterAI		-0.021	Neutral
Varity_R		0.15
gMVP		0.68
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;