20-45095187-C-A

Position:

• chr20-45095187-C-A

Variant summary

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

The NM_001322799.2(KCNS1):​c.1264G>T​(p.Val422Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNS1 NM_001322799.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

KCNS1 (HGNC:6300): (potassium voltage-gated channel modifier subfamily S member 1) 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. [provided by RefSeq, Jul 2008]

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, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNS1	NM_001322799.2	c.1264G>T	p.Val422Leu	missense_variant	4/4	ENST00000537075.3	NP_001309728.1
KCNS1	NM_002251.5	c.1264G>T	p.Val422Leu	missense_variant	5/5		NP_002242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNS1	ENST00000537075.3	c.1264G>T	p.Val422Leu	missense_variant	4/4	1	NM_001322799.2	ENSP00000445595.1
KCNS1	ENST00000306117.5	c.1264G>T	p.Val422Leu	missense_variant	5/5	1		ENSP00000307694.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Feb 22, 2023

The c.1264G>T (p.V422L) alteration is located in exon 5 (coding exon 3) of the KCNS1 gene. This alteration results from a G to T substitution at nucleotide position 1264, causing the valine (V) at amino acid position 422 to be replaced by a leucine (L). 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.96	D;D
Vest4		0.86
MutPred		0.85		Loss of glycosylation at T421 (P = 0.0983);Loss of glycosylation at T421 (P = 0.0983);
MVP		0.98
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.63
gMVP		0.94

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: chr20-43723828;