2-17931618-G-A

Variant summary

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

The NM_002252.5(KCNS3):c.610G>A(p.Val204Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: KCNS3 NM_002252.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34

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=0.07653028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNS3	NM_002252.5	c.610G>A	p.Val204Ile	missense_variant	3/3	ENST00000304101.9
KCNS3	NM_001282428.2	c.610G>A	p.Val204Ile	missense_variant	3/3
KCNS3	XM_011532825.2	c.610G>A	p.Val204Ile	missense_variant	4/4
KCNS3	XM_047444255.1	c.610G>A	p.Val204Ile	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNS3	ENST00000304101.9	c.610G>A	p.Val204Ile	missense_variant	3/3	1	NM_002252.5	P1
KCNS3	ENST00000403915.5	c.610G>A	p.Val204Ile	missense_variant	3/3	1		P1
KCNS3	ENST00000465292.5	n.305+13747G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152184 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000115 AC: 29 AN: 251250 Hom.: 0 AF XY: 0.0000737 AC XY: 10 AN XY: 135776

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000581 AC: 85 AN: 1461878 Hom.: 0 Cov.: 41 AF XY: 0.0000536 AC XY: 39 AN XY: 727234

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000374

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152184 Hom.: 0 Cov.: 31 AF XY: 0.000229 AC XY: 17 AN XY: 74338

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000153 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000218

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

Jun 24, 2022

The c.610G>A (p.V204I) 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 610, causing the valine (V) at amino acid position 204 to be replaced by an isoleucine (I). 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	0.060
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	1.6
Dann	Benign	0.86
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.44	N
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.077	T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.68	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.36	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.0010	B;B
Vest4		0.087
MVP		0.72
MPC		0.27
ClinPred		0.019	T
GERP RS		-2.3
Varity_R		0.011
gMVP		0.13

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: rs144701569; hg19: chr2-18112885; COSMIC: COSV58405792; COSMIC: COSV58405792;