2-17931069-G-T

Variant names:

• chr2-17931069-G-T
• NM_002252.5:c.61G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002252.5(KCNS3):​c.61G>T​(p.Val21Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 6.8e-7 (0 hom.)
• Consequence: KCNS3 NM_002252.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.12

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNS3	NM_002252.5	c.61G>T	p.Val21Leu	missense_variant	Exon 3 of 3	ENST00000304101.9	NP_002243.3
KCNS3	NM_001282428.2	c.61G>T	p.Val21Leu	missense_variant	Exon 3 of 3		NP_001269357.1
KCNS3	XM_011532825.2	c.61G>T	p.Val21Leu	missense_variant	Exon 4 of 4		XP_011531127.1
KCNS3	XM_047444255.1	c.61G>T	p.Val21Leu	missense_variant	Exon 3 of 3		XP_047300211.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNS3	ENST00000304101.9	c.61G>T	p.Val21Leu	missense_variant	Exon 3 of 3	1	NM_002252.5	ENSP00000305824.4
KCNS3	ENST00000403915.5	c.61G>T	p.Val21Leu	missense_variant	Exon 3 of 3	1		ENSP00000385968.1
KCNS3	ENST00000419802.1	c.61G>T	p.Val21Leu	missense_variant	Exon 3 of 3	3		ENSP00000400098.1
KCNS3	ENST00000465292.5	n.305+13198G>T		intron_variant	Intron 2 of 4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.6	H;H;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.76
MutPred		0.85		Loss of methylation at K25 (P = 0.0907);Loss of methylation at K25 (P = 0.0907);Loss of methylation at K25 (P = 0.0907);
MVP		0.98
MPC		1.0
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.70
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-18112336;