rs201784750

Positions:

• chr1-201075540-T-A
• chr1-201075540-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000069.3(CACNA1S):​c.1903A>T​(p.Met635Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. M635K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.564

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26583922).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.1903A>T	p.Met635Leu	missense_variant	13/44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.1903A>T	p.Met635Leu	missense_variant	13/43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.1903A>T	p.Met635Leu	missense_variant	13/44	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	8.4
DANN	Benign	0.76
DEOGEN2	Uncertain	0.50	D;D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	0.81	.;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.040	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.0	.;B
Vest4		0.39
MutPred		0.56		Gain of catalytic residue at M635 (P = 0.0636);Gain of catalytic residue at M635 (P = 0.0636);
MVP		0.66
MPC		0.10
ClinPred		0.16	T
GERP RS		-3.1
Varity_R		0.15
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201784750; hg19: chr1-201044668;