chr1-201091736-C-A

Position:

• chr1-201091736-C-A

Variant summary

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

The NM_000069.3(CACNA1S):​c.598G>T​(p.Ala200Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A200T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.93

Genes affected

CACNA1S (HGNC:1397): (calcium voltage-gated channel subunit alpha1 S) This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.598G>T	p.Ala200Ser	missense_variant	5/44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.598G>T	p.Ala200Ser	missense_variant	5/43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.598G>T	p.Ala200Ser	missense_variant	5/44	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	.;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.025	D;D
Sift4G	Benign	0.077	T;T
Polyphen		0.20	.;B
Vest4		0.54
MutPred		0.61		Gain of catalytic residue at L196 (P = 0.0858);Gain of catalytic residue at L196 (P = 0.0858);
MVP		0.93
MPC		0.22
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.43
gMVP		0.66

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: rs527702358; hg19: chr1-201060864;