Genetic Variant NM_002252.5:c.604A>T (chr2-17931612-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002252.5(KCNS3):c.604A>T(p.Met202Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KCNS3
NM_002252.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.32

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNS3	NM_002252.5 link	c.604A>T	p.Met202Leu	missense_variant	Exon 3 of 3	ENST00000304101.9	NP_002243.3	Q9BQ31
KCNS3	NM_001282428.2 link	c.604A>T	p.Met202Leu	missense_variant	Exon 3 of 3		NP_001269357.1	Q9BQ31
KCNS3	XM_011532825.2 link	c.604A>T	p.Met202Leu	missense_variant	Exon 4 of 4		XP_011531127.1	Q9BQ31
KCNS3	XM_047444255.1 link	c.604A>T	p.Met202Leu	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.604A>T	p.Met202Leu	missense_variant	Exon 3 of 3	1	NM_002252.5	ENSP00000305824.4	Q9BQ31
KCNS3	ENST00000403915.5 link	c.604A>T	p.Met202Leu	missense_variant	Exon 3 of 3	1		ENSP00000385968.1	Q9BQ31
KCNS3	ENST00000465292.5 link	n.305+13741A>T		intron_variant	Intron 2 of 4	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.31

T;T

Eigen

Benign

-0.020

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

1.4

L;L

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.030

N;N

REVEL

Uncertain

0.53

Sift

Benign

0.57

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.038

B;B

Vest4

0.81

MutPred

0.61

Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);

MVP

0.93

MPC

1.0

ClinPred

0.72

GERP RS

6.1

Varity_R

0.18

gMVP

0.70

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over