20-45097799-C-G

Variant names:

• chr20-45097799-C-G
• NM_001322799.2:c.973G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001322799.2(KCNS1):​c.973G>C​(p.Ala325Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNS1 NM_001322799.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.850
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322799.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNS1	NM_001322799.2	MANE Select	c.973G>C	p.Ala325Pro	missense	Exon 3 of 4	NP_001309728.1	Q96KK3
	KCNS1	NM_002251.5		c.973G>C	p.Ala325Pro	missense	Exon 4 of 5	NP_002242.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNS1	ENST00000537075.3	TSL:1 MANE Select	c.973G>C	p.Ala325Pro	missense	Exon 3 of 4	ENSP00000445595.1	Q96KK3
	KCNS1	ENST00000306117.5	TSL:1	c.973G>C	p.Ala325Pro	missense	Exon 4 of 5	ENSP00000307694.1	Q96KK3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.85
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.49
Sift	Benign	0.12	T
Sift4G	Benign	0.33	T
Polyphen		0.85	P
Vest4		0.35
MutPred		0.54		Loss of catalytic residue at A325 (P = 0.027)
MVP		0.92
ClinPred		0.52	D
GERP RS		2.8
Varity_R		0.38
gMVP		0.74
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

hg19: chr20-43726440;