2-17931388-A-G

Position:

• chr2-17931388-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002252.5(KCNS3):​c.380A>G​(p.Glu127Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNS3 NM_002252.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.18

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12874454).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNS3	NM_002252.5	c.380A>G	p.Glu127Gly	missense_variant	3/3	ENST00000304101.9	NP_002243.3
KCNS3	NM_001282428.2	c.380A>G	p.Glu127Gly	missense_variant	3/3		NP_001269357.1
KCNS3	XM_011532825.2	c.380A>G	p.Glu127Gly	missense_variant	4/4		XP_011531127.1
KCNS3	XM_047444255.1	c.380A>G	p.Glu127Gly	missense_variant	3/3		XP_047300211.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNS3	ENST00000304101.9	c.380A>G	p.Glu127Gly	missense_variant	3/3	1	NM_002252.5	ENSP00000305824	P1
KCNS3	ENST00000403915.5	c.380A>G	p.Glu127Gly	missense_variant	3/3	1		ENSP00000385968	P1
KCNS3	ENST00000465292.5	n.305+13517A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2023

The c.380A>G (p.E127G) alteration is located in exon 3 (coding exon 1) of the KCNS3 gene. This alteration results from a A to G substitution at nucleotide position 380, causing the glutamic acid (E) at amino acid position 127 to be replaced by a glycine (G). 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	0.077
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.70	.;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.77	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.13
Sift	Benign	0.25	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.016	B;B
Vest4		0.27
MutPred		0.45		Loss of stability (P = 0.0322);Loss of stability (P = 0.0322);
MVP		0.73
MPC		0.40
ClinPred		0.81	D
GERP RS		5.7
Varity_R		0.096
gMVP		0.36

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: rs1662961721; hg19: chr2-18112655;