rs4240213

Positions:

• chr2-17931206-G-A
• chr2-17931206-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002252.5(KCNS3):​c.198G>A​(p.Glu66Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.965 in 1,614,112 control chromosomes in the GnomAD database, including 752,402 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.94 (66948 hom., cov: 32)
  • Exomes 𝑓: 0.97 (685454 hom.)
• Consequence: KCNS3 NM_002252.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.45

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP7: Synonymous conserved (PhyloP=2.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNS3	NM_002252.5	c.198G>A	p.Glu66Glu	synonymous_variant	3/3	ENST00000304101.9	NP_002243.3
KCNS3	NM_001282428.2	c.198G>A	p.Glu66Glu	synonymous_variant	3/3		NP_001269357.1
KCNS3	XM_011532825.2	c.198G>A	p.Glu66Glu	synonymous_variant	4/4		XP_011531127.1
KCNS3	XM_047444255.1	c.198G>A	p.Glu66Glu	synonymous_variant	3/3		XP_047300211.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNS3	ENST00000304101.9	c.198G>A	p.Glu66Glu	synonymous_variant	3/3	1	NM_002252.5	ENSP00000305824.4
KCNS3	ENST00000403915.5	c.198G>A	p.Glu66Glu	synonymous_variant	3/3	1		ENSP00000385968.1
KCNS3	ENST00000419802.1	c.198G>A	p.Glu66Glu	synonymous_variant	3/3	3		ENSP00000400098.1
KCNS3	ENST00000465292.5	n.305+13335G>A		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.936 AC: 142359 AN: 152114 Hom.: 66894 Cov.: 32

Gnomad AFR AF: 0.842

Gnomad AMI AF: 0.968

Gnomad AMR AF: 0.966

Gnomad ASJ AF: 0.957

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.989

Gnomad FIN AF: 0.979

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.969

Gnomad OTH AF: 0.938

GnomAD3 exomes AF: 0.966 AC: 243010 AN: 251476 Hom.: 117552 AF XY: 0.969 AC XY: 131677 AN XY: 135912

Gnomad AFR exome AF: 0.840

Gnomad AMR exome AF: 0.980

Gnomad ASJ exome AF: 0.954

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.987

Gnomad FIN exome AF: 0.979

Gnomad NFE exome AF: 0.968

Gnomad OTH exome AF: 0.967

GnomAD4 exome AF: 0.968 AC: 1415260 AN: 1461880 Hom.: 685454 Cov.: 63 AF XY: 0.969 AC XY: 704776 AN XY: 727246

Gnomad4 AFR exome AF: 0.835

Gnomad4 AMR exome AF: 0.978

Gnomad4 ASJ exome AF: 0.954

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.987

Gnomad4 FIN exome AF: 0.978

Gnomad4 NFE exome AF: 0.969

Gnomad4 OTH exome AF: 0.961

GnomAD4 genome AF: 0.936 AC: 142471 AN: 152232 Hom.: 66948 Cov.: 32 AF XY: 0.939 AC XY: 69888 AN XY: 74450

Gnomad4 AFR AF: 0.842

Gnomad4 AMR AF: 0.966

Gnomad4 ASJ AF: 0.957

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.989

Gnomad4 FIN AF: 0.979

Gnomad4 NFE AF: 0.969

Gnomad4 OTH AF: 0.938

Alfa AF: 0.960 Hom.: 91773

Bravo AF: 0.930

Asia WGS AF: 0.987 AC: 3433 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.6
DANN	Benign	0.46

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: rs4240213; hg19: chr2-18112473;