2-17932153-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002252.5(KCNS3):c.1145C>T(p.Ala382Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,613,920 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0058 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (13 hom.)
• Consequence: KCNS3 NM_002252.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.665

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012160063).
• BP6: Variant 2-17932153-C-T is Benign according to our data. Variant chr2-17932153-C-T is described in ClinVar as [Benign]. Clinvar id is 789964.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0058 (882/152074) while in subpopulation AFR AF= 0.0187 (777/41468). AF 95% confidence interval is 0.0176. There are 5 homozygotes in gnomad4. There are 422 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNS3	NM_002252.5	c.1145C>T	p.Ala382Val	missense_variant	3/3	ENST00000304101.9
KCNS3	NM_001282428.2	c.1145C>T	p.Ala382Val	missense_variant	3/3
KCNS3	XM_011532825.2	c.1145C>T	p.Ala382Val	missense_variant	4/4
KCNS3	XM_047444255.1	c.1145C>T	p.Ala382Val	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNS3	ENST00000304101.9	c.1145C>T	p.Ala382Val	missense_variant	3/3	1	NM_002252.5	P1
KCNS3	ENST00000403915.5	c.1145C>T	p.Ala382Val	missense_variant	3/3	1		P1
KCNS3	ENST00000465292.5	n.305+14282C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 874 AN: 151956 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00176 AC: 443 AN: 251224 Hom.: 4 AF XY: 0.00143 AC XY: 194 AN XY: 135762

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000379

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000750 AC: 1096 AN: 1461846 Hom.: 13 Cov.: 41 AF XY: 0.000675 AC XY: 491 AN XY: 727218

Gnomad4 AFR exome AF: 0.0184

Gnomad4 AMR exome AF: 0.00279

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000185

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00580 AC: 882 AN: 152074 Hom.: 5 Cov.: 32 AF XY: 0.00568 AC XY: 422 AN XY: 74344

Gnomad4 AFR AF: 0.0187

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00110 Hom.: 1

Bravo AF: 0.00725

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0229 AC: 101

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00187 AC: 227

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	10
Dann	Benign	0.87
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.096	N
MetaRNN	Benign	0.012	T;T
MetaSVM	Uncertain	0.044	D
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.020	N;N
REVEL	Benign	0.28
Sift	Benign	0.26	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.061
MVP		0.89
MPC		0.33
ClinPred		0.0016	T
GERP RS		-0.094
Varity_R		0.020
gMVP		0.75

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: rs34658212; hg19: chr2-18113420;