1-201092059-T-G

Variant names:

• chr1-201092059-T-G
• rs369332959
• NM_000069.3:c.454A>C

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.454A>C​(p.Met152Leu) 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. 13/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M152V) 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: -2.32
• 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=0.054244936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.454A>C	p.Met152Leu	missense_variant	Exon 4 of 44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.454A>C	p.Met152Leu	missense_variant	Exon 4 of 43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.454A>C	p.Met152Leu	missense_variant	Exon 4 of 44	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	0.14
DANN	Benign	0.69
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.53	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	-0.69	.;N
PhyloP100		-2.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.24	N;N
REVEL	Uncertain	0.35
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.23
MutPred		0.39		Loss of disorder (P = 0.0926);Loss of disorder (P = 0.0926);
MVP		0.55
MPC		0.098
ClinPred		0.046	T
GERP RS		-1.8
Varity_R		0.10
gMVP		0.31
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs369332959; hg19: chr1-201061187;