dbSNP rs734784: KCNS1:p.Ile489Val (chr20-45094986-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001322799.2(KCNS1):c.1465A>G(p.Ile489Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 1,613,382 control chromosomes in the GnomAD database, including 160,825 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.47 ( 17379 hom., cov: 29)

Exomes 𝑓: 0.44 ( 143446 hom. )

Consequence

KCNS1
NM_001322799.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.514

Variant links:

Genes affected

KCNS1 (HGNC:6300): (potassium voltage-gated channel modifier subfamily S member 1) 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. [provided by RefSeq, Jul 2008]

KCNS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.79946E-5).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNS1	NM_001322799.2 link	c.1465A>G	p.Ile489Val	missense_variant	Exon 4 of 4	ENST00000537075.3	NP_001309728.1	Q96KK3A2RUL8
KCNS1	NM_002251.5 link	c.1465A>G	p.Ile489Val	missense_variant	Exon 5 of 5		NP_002242.2	Q96KK3A2RUL8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNS1	ENST00000537075.3 link	c.1465A>G	p.Ile489Val	missense_variant	Exon 4 of 4	1	NM_001322799.2	ENSP00000445595.1		Q96KK3
KCNS1	ENST00000306117.5 link	c.1465A>G	p.Ile489Val	missense_variant	Exon 5 of 5	1		ENSP00000307694.1		Q96KK3

Frequencies

GnomAD3 genomes

AF:

0.470

AC:

71250

AN:

151550

Hom.:

17340

Cov.:

show subpopulations

Gnomad AFR

AF:

0.563

Gnomad AMI

AF:

0.500

Gnomad AMR

AF:

0.415

Gnomad ASJ

AF:

0.400

Gnomad EAS

AF:

0.197

Gnomad SAS

AF:

0.290

Gnomad FIN

AF:

0.539

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.451

Gnomad OTH

AF:

0.488

GnomAD3 exomes

AF:

0.409

AC:

102918

AN:

251364

Hom.:

22515

AF XY:

0.408

AC XY:

55480

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.565

Gnomad AMR exome

AF:

0.314

Gnomad ASJ exome

AF:

0.404

Gnomad EAS exome

AF:

0.196

Gnomad SAS exome

AF:

0.305

Gnomad FIN exome

AF:

0.525

Gnomad NFE exome

AF:

0.457

Gnomad OTH exome

AF:

0.422

GnomAD4 exome

AF:

0.437

AC:

638464

AN:

1461714

Hom.:

143446

Cov.:

AF XY:

0.433

AC XY:

315022

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.558

Gnomad4 AMR exome

AF:

0.328

Gnomad4 ASJ exome

AF:

0.411

Gnomad4 EAS exome

AF:

0.159

Gnomad4 SAS exome

AF:

0.306

Gnomad4 FIN exome

AF:

0.517

Gnomad4 NFE exome

AF:

0.454

Gnomad4 OTH exome

AF:

0.439

GnomAD4 genome

AF:

0.470

AC:

71344

AN:

151668

Hom.:

17379

Cov.:

AF XY:

0.470

AC XY:

34782

AN XY:

74072

show subpopulations

Gnomad4 AFR

AF:

0.564

Gnomad4 AMR

AF:

0.415

Gnomad4 ASJ

AF:

0.400

Gnomad4 EAS

AF:

0.196

Gnomad4 SAS

AF:

0.292

Gnomad4 FIN

AF:

0.539

Gnomad4 NFE

AF:

0.451

Gnomad4 OTH

AF:

0.491

Alfa

AF:

0.447

Hom.:

31460

Bravo

AF:

0.467

TwinsUK

AF:

0.456

AC:

1692

ALSPAC

AF:

0.460

AC:

1773

ESP6500AA

AF:

0.565

AC:

2490

ESP6500EA

AF:

0.450

AC:

3866

ExAC

AF:

0.413

AC:

50106

Asia WGS

AF:

0.293

AC:

1019

AN:

3478

EpiCase

AF:

0.456

EpiControl

AF:

0.457

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.11

DANN

Benign

0.18

DEOGEN2

Benign

0.056

T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0039

LIST_S2

Benign

0.072

.;T

MetaRNN

Benign

0.000018

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.46

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

0.14

N;N

REVEL

Benign

0.23

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.0070

ClinPred

0.0022

GERP RS

0.29

Varity_R

0.030

gMVP

0.23

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