1-201043356-C-T

Variant names:

• chr1-201043356-C-T
• rs13374149
• NM_000069.3:c.4973G>A

Variant summary

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

The ENST00000362061.4(CACNA1S):​c.4973G>A​(p.Arg1658His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.058 in 1,613,994 control chromosomes in the GnomAD database, including 4,663 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. R1658C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1603 hom., cov: 32)
  • Exomes 𝑓: 0.053 (3060 hom.)
• Consequence: CACNA1S ENST00000362061.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.253
• Publications: 20 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=0.0019210279).
• BP6: Variant 1-201043356-C-T is Benign according to our data. Variant chr1-201043356-C-T is described in ClinVar as Benign. ClinVar VariationId is 254842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000362061.4. 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.4973G>A	p.Arg1658His	missense	Exon 40 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.4973G>A	p.Arg1658His	missense	Exon 40 of 44	ENSP00000355192.3
	CACNA1S	ENST00000367338.7	TSL:5	c.4916G>A	p.Arg1639His	missense	Exon 39 of 43	ENSP00000356307.3
	CACNA1S	ENST00000681874.1		c.4913G>A	p.Arg1638His	missense	Exon 39 of 43	ENSP00000505162.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16326 AN: 152024 Hom.: 1596 Cov.: 32

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0485

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0321

Gnomad FIN AF: 0.0577

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0502

Gnomad OTH AF: 0.0814

GnomAD2 exomes AF: 0.0613 AC: 15403 AN: 251446 AF XY: 0.0577

Gnomad AFR exome AF: 0.271

Gnomad AMR exome AF: 0.0342

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.000762

Gnomad FIN exome AF: 0.0574

Gnomad NFE exome AF: 0.0525

Gnomad OTH exome AF: 0.0637

GnomAD4 exome AF: 0.0528 AC: 77180 AN: 1461852 Hom.: 3060 Cov.: 31 AF XY: 0.0516 AC XY: 37498 AN XY: 727224

African (AFR) AF: 0.268 AC: 8984 AN: 33476

American (AMR) AF: 0.0375 AC: 1675 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 2625 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39686

South Asian (SAS) AF: 0.0371 AC: 3204 AN: 86258

European-Finnish (FIN) AF: 0.0563 AC: 3006 AN: 53420

Middle Eastern (MID) AF: 0.0928 AC: 535 AN: 5768

European-Non Finnish (NFE) AF: 0.0478 AC: 53182 AN: 1111988

Other (OTH) AF: 0.0656 AC: 3960 AN: 60396

GnomAD4 genome AF: 0.107 AC: 16351 AN: 152142 Hom.: 1603 Cov.: 32 AF XY: 0.106 AC XY: 7861 AN XY: 74368

African (AFR) AF: 0.261 AC: 10833 AN: 41468

American (AMR) AF: 0.0485 AC: 741 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 350 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.0323 AC: 156 AN: 4828

European-Finnish (FIN) AF: 0.0577 AC: 611 AN: 10590

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0502 AC: 3413 AN: 68004

Other (OTH) AF: 0.0806 AC: 170 AN: 2110

Alfa AF: 0.0711 Hom.: 1688

Bravo AF: 0.114

TwinsUK AF: 0.0464 AC: 172

ALSPAC AF: 0.0532 AC: 205

ESP6500AA AF: 0.253 AC: 1116

ESP6500EA AF: 0.0530 AC: 456

ExAC AF: 0.0656 AC: 7965

Asia WGS AF: 0.0270 AC: 94 AN: 3478

EpiCase AF: 0.0517

EpiControl AF: 0.0508

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)
-	-	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	Benign	0.083
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.0073	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.25
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.24
Sift	Benign	0.31	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.043
MPC		0.13
ClinPred		0.031	T
GERP RS		1.6
Varity_R		0.090
gMVP		0.50
Mutation Taster		=99/1	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: rs13374149; hg19: chr1-201012484; COSMIC: COSV62942163; COSMIC: COSV62942163;