8-98428784-G-A

Position:

chr8-98428784-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.56

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:

STK3 (HGNC:):

STK3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 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_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNS2	NM_020697.4 linkuse as main transcript	c.805G>A	p.Val269Ile	missense_variant	2/2	ENST00000287042.5	NP_065748.1	Q9ULS6
STK3	XM_047422133.1 linkuse as main transcript	c.1423+8319C>T		intron_variant			XP_047278089.1
STK3	XR_007060752.1 linkuse as main transcript	n.1571+8319C>T		intron_variant
STK3	XR_007060753.1 linkuse as main transcript	n.1571+8319C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNS2	ENST00000287042.5 linkuse as main transcript	c.805G>A	p.Val269Ile	missense_variant	2/2	1	NM_020697.4	ENSP00000287042.4	Q9ULS6
KCNS2	ENST00000521839.1 linkuse as main transcript	c.805G>A	p.Val269Ile	missense_variant	2/2	5		ENSP00000430712.1	Q9ULS6
STK3	ENST00000517832.1 linkuse as main transcript	n.483+5343C>T		intron_variant		3
STK3	ENST00000649151.1 linkuse as main transcript	n.427+5343C>T		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00203

AC:

309

AN:

152114

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000486

AC XY:

AN XY:

135922

show subpopulations

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.:

Cov.:

AF XY:

0.000177

AC XY:

129

AN XY:

727246

show subpopulations

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.:

Cov.:

AF XY:

0.00184

AC XY:

137

AN XY:

74424

show subpopulations

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.:

Bravo

AF:

0.00231

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000725

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Uncertain

0.47

T;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.73

.;T

M_CAP

Benign

0.055

MetaRNN

Benign

0.013

T;T

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

-0.095

N;N

PrimateAI

Uncertain

0.54

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over