1-201059277-A-G

Variant names:

• chr1-201059277-A-G
• rs763707356
• NM_000069.3:c.3437T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_000069.3(CACNA1S):​c.3437T>C​(p.Met1146Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. M1146K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.26
• Publications: 0 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):

• hypokalemic periodic paralysis, type 1

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital myopathy 18

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

  Inheritance: SD, AD, AR 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39591676).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000069.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	NM_000069.3	MANE Select	c.3437T>C	p.Met1146Thr	missense	Exon 27 of 44	NP_000060.2	Q13698

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	ENST00000362061.4	TSL:1 MANE Select	c.3437T>C	p.Met1146Thr	missense	Exon 27 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.3437T>C	p.Met1146Thr	missense	Exon 27 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.3377T>C	p.Met1126Thr	missense	Exon 26 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461356 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727034

African (AFR) AF: 0.0000598 AC: 2 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111570

Other (OTH) AF: 0.0000166 AC: 1 AN: 60376

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.038
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.0	L
PhyloP100		6.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.45
Sift	Benign	0.036	D
Sift4G	Uncertain	0.039	D
Polyphen		0.0040	B
Vest4		0.48
MutPred		0.36		Gain of disorder (P = 0.0722)
MVP		0.93
MPC		0.12
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.35
gMVP		0.70
Mutation Taster		=84/16	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: rs763707356; hg19: chr1-201028405;