8-98428784-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_020697.4(KCNS2):c.805G>A(p.Val269Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,614,126 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (4 hom.)
• Consequence: KCNS2 NM_020697.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.56

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012956023).
• BP6: Variant 8-98428784-G-A is Benign according to our data. Variant chr8-98428784-G-A is described in ClinVar as [Benign]. Clinvar id is 723919.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNS2	NM_020697.4	c.805G>A	p.Val269Ile	missense_variant	2/2	ENST00000287042.5
STK3	XM_047422133.1	c.1423+8319C>T		intron_variant
STK3	XR_007060752.1	n.1571+8319C>T		intron_variant, non_coding_transcript_variant
STK3	XR_007060753.1	n.1571+8319C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNS2	ENST00000287042.5	c.805G>A	p.Val269Ile	missense_variant	2/2	1	NM_020697.4	P1
KCNS2	ENST00000521839.1	c.805G>A	p.Val269Ile	missense_variant	2/2	5		P1
STK3	ENST00000517832.1	n.483+5343C>T		intron_variant, non_coding_transcript_variant		3
STK3	ENST00000649151.1	n.427+5343C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00203 AC: 309 AN: 152114 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00712

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000577 AC: 145 AN: 251496 Hom.: 2 AF XY: 0.000486 AC XY: 66 AN XY: 135922

Gnomad AFR exome AF: 0.00769

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000209 AC: 305 AN: 1461892 Hom.: 4 Cov.: 32 AF XY: 0.000177 AC XY: 129 AN XY: 727246

Gnomad4 AFR exome AF: 0.00687

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152234 Hom.: 2 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74424

Gnomad4 AFR AF: 0.00710

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000468 Hom.: 1

Bravo AF: 0.00231

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000725 AC: 88

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	19
Dann	Benign	0.92
DEOGEN2	Uncertain	0.47	T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	-0.095	N;N
MutationTaster	Benign	0.66	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.71	N;N
REVEL	Benign	0.28
Sift	Benign	0.16	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0	B;B
Vest4		0.048
MVP		0.39
MPC		0.47
ClinPred		0.0057	T
GERP RS		4.0
Varity_R		0.037
gMVP		0.39

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

Other links and lift over

dbSNP: rs142144460; hg19: chr8-99441012; COSMIC: COSV54637201;