chr1-201043375-G-C

Variant names:

• chr1-201043375-G-C
• rs143933255
• NM_000069.3:c.4954C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000069.3(CACNA1S):​c.4954C>G​(p.Arg1652Gly) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1652H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.267
• Publications: 1 publications found

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]

CACNA1S Gene-Disease associations (from GenCC):

• congenital myopathy 18

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypokalemic periodic paralysis, type 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• malignant hyperthermia, susceptibility to, 5

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital myopathy

  Inheritance: SD, AR, AD Classification: STRONG Submitted by: Illumina, Genomics England PanelApp
• hypokalemic periodic paralysis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059303522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.4954C>G	p.Arg1652Gly	missense_variant	Exon 40 of 44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.4897C>G	p.Arg1633Gly	missense_variant	Exon 39 of 43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.4954C>G	p.Arg1652Gly	missense_variant	Exon 40 of 44	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4954C>G (p.R1652G) alteration is located in exon 40 (coding exon 40) of the CACNA1S gene. This alteration results from a C to G substitution at nucleotide position 4954, causing the arginine (R) at amino acid position 1652 to be replaced by a glycine (G). 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	Benign	0.069
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	1.1
DANN	Benign	0.84
DEOGEN2	Benign	0.0089	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.69	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.059	T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.0	.;N
PhyloP100		0.27
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.21
Sift	Benign	0.49	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0	.;B
Vest4		0.049
MutPred		0.24		.;Gain of catalytic residue at R1652 (P = 0.0536);
MVP		0.75
MPC		0.14
ClinPred		0.12	T
GERP RS		-3.6
Varity_R		0.062
gMVP		0.53
Mutation Taster		=87/13	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

dbSNP: rs143933255; hg19: chr1-201012503;