chr1-201040054-A-G

Variant names:

• chr1-201040054-A-G
• rs12139527
• NM_000069.3:c.5399T>C

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.5399T>C​(p.Leu1800Ser) variant causes a missense change. The variant allele was found at a frequency of 0.146 in 1,614,082 control chromosomes in the GnomAD database, including 24,387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1800L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (7242 hom., cov: 34)
  • Exomes 𝑓: 0.14 (17145 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.82
• Publications: 40 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=0.0020485818).
• BP6: Variant 1-201040054-A-G is Benign according to our data. Variant chr1-201040054-A-G is described in ClinVar as Benign. ClinVar VariationId is 254847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.537 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	NM_000069.3	MANE Select	c.5399T>C	p.Leu1800Ser	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.5399T>C	p.Leu1800Ser	missense	Exon 44 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.5342T>C	p.Leu1781Ser	missense	Exon 43 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.5339T>C	p.Leu1780Ser	missense	Exon 43 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37109 AN: 152104 Hom.: 7235 Cov.: 34

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0697

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.197

GnomAD2 exomes AF: 0.147 AC: 36827 AN: 250696 AF XY: 0.138

Gnomad AFR exome AF: 0.560

Gnomad AMR exome AF: 0.0878

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.125

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.149

GnomAD4 exome AF: 0.136 AC: 199110 AN: 1461860 Hom.: 17145 Cov.: 34 AF XY: 0.133 AC XY: 96807 AN XY: 727234

African (AFR) AF: 0.559 AC: 18702 AN: 33480

American (AMR) AF: 0.0948 AC: 4239 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 4090 AN: 26136

East Asian (EAS) AF: 0.120 AC: 4746 AN: 39688

South Asian (SAS) AF: 0.0729 AC: 6285 AN: 86258

European-Finnish (FIN) AF: 0.139 AC: 7408 AN: 53408

Middle Eastern (MID) AF: 0.123 AC: 708 AN: 5768

European-Non Finnish (NFE) AF: 0.129 AC: 143523 AN: 1112002

Other (OTH) AF: 0.156 AC: 9409 AN: 60396

GnomAD4 genome AF: 0.244 AC: 37143 AN: 152222 Hom.: 7242 Cov.: 34 AF XY: 0.238 AC XY: 17750 AN XY: 74446

African (AFR) AF: 0.543 AC: 22527 AN: 41500

American (AMR) AF: 0.154 AC: 2363 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 542 AN: 3470

East Asian (EAS) AF: 0.120 AC: 622 AN: 5176

South Asian (SAS) AF: 0.0690 AC: 333 AN: 4828

European-Finnish (FIN) AF: 0.146 AC: 1550 AN: 10616

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8739 AN: 68010

Other (OTH) AF: 0.194 AC: 411 AN: 2114

Alfa AF: 0.163 Hom.: 8345

Bravo AF: 0.261

TwinsUK AF: 0.132 AC: 489

ALSPAC AF: 0.129 AC: 498

ESP6500AA AF: 0.541 AC: 2385

ESP6500EA AF: 0.131 AC: 1124

ExAC AF: 0.155 AC: 18788

Asia WGS AF: 0.118 AC: 409 AN: 3478

EpiCase AF: 0.122

EpiControl AF: 0.126

ClinVar

ClinVar submissions

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)
-	-	1	Congenital myopathy 18 (1)
-	-	1	Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 (1)
-	-	1	not provided (1)
-	-	1	Thyrotoxic periodic paralysis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.076	T
Polyphen		1.0	D
Vest4		0.11
MPC		0.62
ClinPred		0.027	T
GERP RS		4.9
Varity_R		0.15
gMVP		0.56
Mutation Taster		=95/5	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: rs12139527; hg19: chr1-201009182; COSMIC: COSV62942385; COSMIC: COSV62942385;