2-17931558-G-A

Variant names:

• chr2-17931558-G-A
• rs753326896
• NM_002252.5:c.550G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002252.5(KCNS3):​c.550G>A​(p.Ala184Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: KCNS3 NM_002252.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.27

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNS3	NM_002252.5	c.550G>A	p.Ala184Thr	missense_variant	Exon 3 of 3	ENST00000304101.9	NP_002243.3
KCNS3	NM_001282428.2	c.550G>A	p.Ala184Thr	missense_variant	Exon 3 of 3		NP_001269357.1
KCNS3	XM_011532825.2	c.550G>A	p.Ala184Thr	missense_variant	Exon 4 of 4		XP_011531127.1
KCNS3	XM_047444255.1	c.550G>A	p.Ala184Thr	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.550G>A	p.Ala184Thr	missense_variant	Exon 3 of 3	1	NM_002252.5	ENSP00000305824.4
KCNS3	ENST00000403915.5	c.550G>A	p.Ala184Thr	missense_variant	Exon 3 of 3	1		ENSP00000385968.1
KCNS3	ENST00000465292.5	n.305+13687G>A		intron_variant	Intron 2 of 4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251154 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135732

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461858 Hom.: 0 Cov.: 41 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.550G>A (p.A184T) alteration is located in exon 3 (coding exon 1) of the KCNS3 gene. This alteration results from a G to A substitution at nucleotide position 550, causing the alanine (A) at amino acid position 184 to be replaced by a threonine (T). 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	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	.;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.98	D;D
Vest4		0.59
MutPred		0.74		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		1.0
MPC		0.67
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.42
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

Other links and lift over

dbSNP: rs753326896; hg19: chr2-18112825; COSMIC: COSV58405873; COSMIC: COSV58405873;