Genetic Variant NM_002252.5:c.565A>G (chr2-17931573-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002252.5(KCNS3):c.565A>G(p.Ile189Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000464 in 1,614,148 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

KCNS3
NM_002252.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.594

Variant links:

Genes affected

KCNS3 (HGNC:6302): (potassium voltage-gated channel modifier subfamily S member 3) Voltage-gated potassium channels form the largest and most diversified class of ion channels and are present in both excitable and nonexcitable cells. Their main functions are associated with the regulation of the resting membrane potential and the control of the shape and frequency of action potentials. The alpha subunits are of 2 types: those that are functional by themselves and those that are electrically silent but capable of modulating the activity of specific functional alpha subunits. The protein encoded by this gene is not functional by itself but can form heteromultimers with member 1 and with member 2 (and possibly other members) of the Shab-related subfamily of potassium voltage-gated channel proteins. This gene belongs to the S subfamily of the potassium channel family. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]

KCNS3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007483721).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNS3	NM_002252.5 link	c.565A>G	p.Ile189Val	missense_variant	Exon 3 of 3	ENST00000304101.9	NP_002243.3	Q9BQ31
KCNS3	NM_001282428.2 link	c.565A>G	p.Ile189Val	missense_variant	Exon 3 of 3		NP_001269357.1	Q9BQ31
KCNS3	XM_011532825.2 link	c.565A>G	p.Ile189Val	missense_variant	Exon 4 of 4		XP_011531127.1	Q9BQ31
KCNS3	XM_047444255.1 link	c.565A>G	p.Ile189Val	missense_variant	Exon 3 of 3		XP_047300211.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNS3	ENST00000304101.9 link	c.565A>G	p.Ile189Val	missense_variant	Exon 3 of 3	1	NM_002252.5	ENSP00000305824.4	Q9BQ31
KCNS3	ENST00000403915.5 link	c.565A>G	p.Ile189Val	missense_variant	Exon 3 of 3	1		ENSP00000385968.1	Q9BQ31
KCNS3	ENST00000465292.5 link	n.305+13702A>G		intron_variant	Intron 2 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.00225

AC:

343

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000645

AC:

162

AN:

251230

Hom.:

AF XY:

0.000493

AC XY:

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.00874

Gnomad AMR exome

AF:

0.000434

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:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000278

AC:

406

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

189

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00914

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.00225

AC:

343

AN:

152276

Hom.:

Cov.:

AF XY:

0.00232

AC XY:

173

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00794

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:

0.000945

Alfa

AF:

0.000361

Hom.:

Bravo

AF:

0.00263

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000758

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

1.3

DANN

Benign

0.82

DEOGEN2

Benign

0.28

T;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.60

.;T

MetaRNN

Benign

0.0075

T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

0.40

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.090

N;N

REVEL

Benign

0.21

Sift

Benign

0.88

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.063

MVP

0.74

MPC

0.28

ClinPred

0.0049

GERP RS

2.0

Varity_R

0.012

gMVP

0.13

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over