chr2-17931228-T-G

Position:

• chr2-17931228-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002252.5(KCNS3):​c.220T>G​(p.Ser74Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: KCNS3 NM_002252.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.97

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3867523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNS3	NM_002252.5	c.220T>G	p.Ser74Ala	missense_variant	3/3	ENST00000304101.9	NP_002243.3
KCNS3	NM_001282428.2	c.220T>G	p.Ser74Ala	missense_variant	3/3		NP_001269357.1
KCNS3	XM_011532825.2	c.220T>G	p.Ser74Ala	missense_variant	4/4		XP_011531127.1
KCNS3	XM_047444255.1	c.220T>G	p.Ser74Ala	missense_variant	3/3		XP_047300211.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNS3	ENST00000304101.9	c.220T>G	p.Ser74Ala	missense_variant	3/3	1	NM_002252.5	ENSP00000305824.4
KCNS3	ENST00000403915.5	c.220T>G	p.Ser74Ala	missense_variant	3/3	1		ENSP00000385968.1
KCNS3	ENST00000419802.1	c.220T>G	p.Ser74Ala	missense_variant	3/3	3		ENSP00000400098.1
KCNS3	ENST00000465292.5	n.305+13357T>G		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461836 Hom.: 0 Cov.: 42 AF XY: 0.00000413 AC XY: 3 AN XY: 727222

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Dec 07, 2024

The c.220T>G (p.S74A) alteration is located in exon 3 (coding exon 1) of the KCNS3 gene. This alteration results from a T to G substitution at nucleotide position 220, causing the serine (S) at amino acid position 74 to be replaced by an alanine (A). 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	0.075
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;T;.
Eigen	Benign	-0.031
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.26	.;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.90	L;L;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.44	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.80	T;T;T
Polyphen		0.45	B;B;.
Vest4		0.38
MutPred		0.44		Loss of phosphorylation at S74 (P = 0.0811);Loss of phosphorylation at S74 (P = 0.0811);Loss of phosphorylation at S74 (P = 0.0811);
MVP		0.89
MPC		0.55
ClinPred		0.58	D
GERP RS		5.7
Varity_R		0.11
gMVP		0.22

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: rs762883850; hg19: chr2-18112495;