chr1-201047168-G-A

Variant names:

• chr1-201047168-G-A
• rs3850625
• NM_000069.3:c.4615C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000069.3(CACNA1S):​c.4615C>T​(p.Arg1539Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,613,950 control chromosomes in the GnomAD database, including 12,268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1539H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.090 (826 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11442 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 7.71
• Publications: 78 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017214417).
• BP6: Variant 1-201047168-G-A is Benign according to our data. Variant chr1-201047168-G-A is described in ClinVar as Benign. ClinVar VariationId is 197021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	NM_000069.3	MANE Select	c.4615C>T	p.Arg1539Cys	missense	Exon 38 of 44	NP_000060.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	ENST00000362061.4	TSL:1 MANE Select	c.4615C>T	p.Arg1539Cys	missense	Exon 38 of 44	ENSP00000355192.3
	CACNA1S	ENST00000367338.7	TSL:5	c.4558C>T	p.Arg1520Cys	missense	Exon 37 of 43	ENSP00000356307.3
	CACNA1S	ENST00000681874.1		c.4555C>T	p.Arg1519Cys	missense	Exon 37 of 43	ENSP00000505162.1

Frequencies

GnomAD3 genomes AF: 0.0905 AC: 13769 AN: 152082 Hom.: 823 Cov.: 33

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.0809

Gnomad ASJ AF: 0.0916

Gnomad EAS AF: 0.0360

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.0961

GnomAD2 exomes AF: 0.116 AC: 29089 AN: 251466 AF XY: 0.125

Gnomad AFR exome AF: 0.0205

Gnomad AMR exome AF: 0.0958

Gnomad ASJ exome AF: 0.0926

Gnomad EAS exome AF: 0.0333

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.119 AC: 174449 AN: 1461750 Hom.: 11442 Cov.: 33 AF XY: 0.123 AC XY: 89401 AN XY: 727178

African (AFR) AF: 0.0183 AC: 614 AN: 33474

American (AMR) AF: 0.0955 AC: 4270 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0910 AC: 2378 AN: 26134

East Asian (EAS) AF: 0.0352 AC: 1396 AN: 39686

South Asian (SAS) AF: 0.211 AC: 18160 AN: 86254

European-Finnish (FIN) AF: 0.152 AC: 8127 AN: 53412

Middle Eastern (MID) AF: 0.110 AC: 637 AN: 5766

European-Non Finnish (NFE) AF: 0.119 AC: 132257 AN: 1111906

Other (OTH) AF: 0.109 AC: 6610 AN: 60394

GnomAD4 genome AF: 0.0905 AC: 13771 AN: 152200 Hom.: 826 Cov.: 33 AF XY: 0.0921 AC XY: 6851 AN XY: 74398

African (AFR) AF: 0.0214 AC: 891 AN: 41556

American (AMR) AF: 0.0806 AC: 1233 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0916 AC: 318 AN: 3472

East Asian (EAS) AF: 0.0367 AC: 190 AN: 5180

South Asian (SAS) AF: 0.193 AC: 931 AN: 4816

European-Finnish (FIN) AF: 0.148 AC: 1565 AN: 10562

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8188 AN: 68004

Other (OTH) AF: 0.0960 AC: 203 AN: 2114

Alfa AF: 0.109 Hom.: 3829

Bravo AF: 0.0809

TwinsUK AF: 0.125 AC: 465

ALSPAC AF: 0.127 AC: 490

ESP6500AA AF: 0.0218 AC: 96

ESP6500EA AF: 0.124 AC: 1065

ExAC AF: 0.117 AC: 14232

Asia WGS AF: 0.106 AC: 370 AN: 3478

EpiCase AF: 0.119

EpiControl AF: 0.120

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Malignant hyperthermia, susceptibility to, 5 (3)
-	-	3	not specified (3)
-	-	2	Hypokalemic periodic paralysis, type 1 (2)
-	-	2	not provided (2)
-	-	1	Congenital myopathy 18 (1)
-	-	1	Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 (1)
-	-	1	Thyrotoxic periodic paralysis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Benign	0.28
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.023	D
Polyphen		0.74	P
Vest4		0.14
MPC		0.38
ClinPred		0.062	T
GERP RS		5.2
Varity_R		0.71
gMVP		0.80
Mutation Taster		=64/36	polymorphism (auto)

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: rs3850625; hg19: chr1-201016296; COSMIC: COSV62938023; COSMIC: COSV62938023;