2-17932348-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002252.5(KCNS3):c.1340G>A(p.Arg447Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R447W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: KCNS3 NM_002252.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058959365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNS3	NM_002252.5	c.1340G>A	p.Arg447Gln	missense_variant	3/3	ENST00000304101.9
KCNS3	NM_001282428.2	c.1340G>A	p.Arg447Gln	missense_variant	3/3
KCNS3	XM_011532825.2	c.1340G>A	p.Arg447Gln	missense_variant	4/4
KCNS3	XM_047444255.1	c.1340G>A	p.Arg447Gln	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNS3	ENST00000304101.9	c.1340G>A	p.Arg447Gln	missense_variant	3/3	1	NM_002252.5	P1
KCNS3	ENST00000403915.5	c.1340G>A	p.Arg447Gln	missense_variant	3/3	1		P1
KCNS3	ENST00000465292.5	n.305+14477G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 251240 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135768

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000208 AC: 304 AN: 1461794 Hom.: 0 Cov.: 41 AF XY: 0.000191 AC XY: 139 AN XY: 727194

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000630

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000219

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74438

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00169 Hom.: 0

Bravo AF: 0.000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

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

Jan 26, 2022

The c.1340G>A (p.R447Q) 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 1340, causing the arginine (R) at amino acid position 447 to be replaced by a glutamine (Q). 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	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	21
Dann	Benign	0.89
DEOGEN2	Benign	0.055	T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.059	T;T
MetaSVM	Uncertain	-0.055	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.47	N;N
REVEL	Benign	0.22
Sift	Benign	0.19	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.20	B;B
Vest4		0.078
MVP		0.96
MPC		0.38
ClinPred		0.019	T
GERP RS		3.4
Varity_R		0.031
gMVP		0.50

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: rs78213799; hg19: chr2-18113615; COSMIC: COSV58408197; COSMIC: COSV58408197;