rs149547196

Variant names:

• chr1-201039938-G-A
• rs149547196
• NM_000069.3:c.5515C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000069.3(CACNA1S):​c.5515C>T​(p.Pro1839Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,614,144 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1839Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0032 (9 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.886
• Publications: 9 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

ENSG00000234132 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004075408).
• BP6: Variant 1-201039938-G-A is Benign according to our data. Variant chr1-201039938-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 294705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00232 (354/152356) while in subpopulation AMR AF = 0.00483 (74/15310). AF 95% confidence interval is 0.00395. There are 1 homozygotes in GnomAd4. There are 157 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR,SD gene

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.5515C>T	p.Pro1839Ser	missense	Exon 44 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.5515C>T	p.Pro1839Ser	missense	Exon 44 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.5458C>T	p.Pro1820Ser	missense	Exon 43 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.5455C>T	p.Pro1819Ser	missense	Exon 43 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 354 AN: 152236 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00243 AC: 611 AN: 251306 AF XY: 0.00236

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00357

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00321 AC: 4698 AN: 1461788 Hom.: 9 Cov.: 31 AF XY: 0.00309 AC XY: 2246 AN XY: 727206

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.00445 AC: 199 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 54 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86258

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53322

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00379 AC: 4212 AN: 1112004

Other (OTH) AF: 0.00295 AC: 178 AN: 60396

GnomAD4 genome AF: 0.00232 AC: 354 AN: 152356 Hom.: 1 Cov.: 34 AF XY: 0.00211 AC XY: 157 AN XY: 74504

African (AFR) AF: 0.000649 AC: 27 AN: 41580

American (AMR) AF: 0.00483 AC: 74 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00347 AC: 236 AN: 68026

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00275 Hom.: 2

Bravo AF: 0.00274

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00230 AC: 279

EpiCase AF: 0.00300

EpiControl AF: 0.00326

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	Malignant hyperthermia, susceptibility to, 5 (3)
-	-	2	Hypokalemic periodic paralysis, type 1 (2)
-	-	2	not specified (2)
-	-	1	CACNA1S-related disorder (1)
-	-	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	0.076
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.095	N
PhyloP100		0.89
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.045
Sift	Benign	0.37	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.022
MVP		0.61
MPC		0.11
ClinPred		0.0032	T
GERP RS		0.13
Varity_R		0.055
gMVP		0.15
Mutation Taster		=99/1	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: rs149547196; hg19: chr1-201009066;