Variant 20-45098231-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001322799.2(KCNS1):c.541C>T(p.Pro181Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000551 in 1,451,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

KCNS1
NM_001322799.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.15

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19577348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNS1	NM_001322799.2 linkuse as main transcript	c.541C>T	p.Pro181Ser	missense_variant	3/4	ENST00000537075.3
KCNS1	NM_002251.5 linkuse as main transcript	c.541C>T	p.Pro181Ser	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNS1	ENST00000537075.3 linkuse as main transcript	c.541C>T	p.Pro181Ser	missense_variant	3/4	1	NM_001322799.2	P1
KCNS1	ENST00000306117.5 linkuse as main transcript	c.541C>T	p.Pro181Ser	missense_variant	4/5	1		P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000133

AC:

AN:

225316

Hom.:

AF XY:

0.0000161

AC XY:

AN XY:

123968

show subpopulations

Gnomad AFR exome

AF:

0.0000739

Gnomad AMR exome

AF:

0.00

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:

0.0000201

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000551

AC:

AN:

1451294

Hom.:

Cov.:

AF XY:

0.00000693

AC XY:

AN XY:

721324

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000632

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000842

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2023

The c.541C>T (p.P181S) alteration is located in exon 4 (coding exon 2) of the KCNS1 gene. This alteration results from a C to T substitution at nucleotide position 541, causing the proline (P) at amino acid position 181 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.066

T;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.91

.;D

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.2

L;L

MutationTaster

Benign

0.82

D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.52

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.49

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.0

B;B

Vest4

0.072

MutPred

0.27

Gain of phosphorylation at P181 (P = 0.0252);Gain of phosphorylation at P181 (P = 0.0252);

MVP

0.82

ClinPred

0.032

GERP RS

3.5

Varity_R

0.068

gMVP

0.63

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