2-17931738-G-T

Variant names:

• chr2-17931738-G-T
• rs367935090
• NM_002252.5:c.730G>T

Variant summary

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

The NM_002252.5(KCNS3):​c.730G>T​(p.Ala244Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,650 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: 0.0000041 (0 hom.)
• Consequence: KCNS3 NM_002252.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.30

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]

ACMG classification

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	c.730G>T	p.Ala244Ser	missense_variant	Exon 3 of 3	ENST00000304101.9	NP_002243.3
KCNS3	NM_001282428.2	c.730G>T	p.Ala244Ser	missense_variant	Exon 3 of 3		NP_001269357.1
KCNS3	XM_011532825.2	c.730G>T	p.Ala244Ser	missense_variant	Exon 4 of 4		XP_011531127.1
KCNS3	XM_047444255.1	c.730G>T	p.Ala244Ser	missense_variant	Exon 3 of 3		XP_047300211.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNS3	ENST00000304101.9	c.730G>T	p.Ala244Ser	missense_variant	Exon 3 of 3	1	NM_002252.5	ENSP00000305824.4
KCNS3	ENST00000403915.5	c.730G>T	p.Ala244Ser	missense_variant	Exon 3 of 3	1		ENSP00000385968.1
KCNS3	ENST00000465292.5	n.305+13867G>T		intron_variant	Intron 2 of 4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250744 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135490

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461650 Hom.: 0 Cov.: 41 AF XY: 0.00000275 AC XY: 2 AN XY: 727080

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	.;T
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	0.83	L;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.89	N;N
REVEL	Uncertain	0.51
Sift	Benign	0.75	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.98	D;D
Vest4		0.48
MutPred		0.70		Gain of methylation at K248 (P = 0.0549);Gain of methylation at K248 (P = 0.0549);
MVP		0.98
MPC		0.89
ClinPred		0.46	T
GERP RS		6.1
Varity_R		0.093
gMVP		0.38

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

Other links and lift over

dbSNP: rs367935090; hg19: chr2-18113005;