chr1-201077916-G-C

Position:

• chr1-201077916-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The ENST00000362061.4(CACNA1S):​c.1582C>G​(p.Arg528Gly) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R528L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1S ENST00000362061.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 3.38

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S4 of repeat II (size 18) in uniprot entity CAC1S_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in ENST00000362061.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-201077916-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 849085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 1-201077916-G-C is Pathogenic according to our data. Variant chr1-201077916-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 21034.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-201077916-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.1582C>G	p.Arg528Gly	missense_variant	11/44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.1582C>G	p.Arg528Gly	missense_variant	11/43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.1582C>G	p.Arg528Gly	missense_variant	11/44	1	NM_000069.3	ENSP00000355192	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypokalemic periodic paralysis, type 1 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	research	Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	Apr 12, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	.;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.92
MutPred		0.84		Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);
MVP		0.97
MPC		0.59
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.93

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: rs80338778; hg19: chr1-201047044;