rs72749169

Variant names:

• chr1-201039883-C-T
• rs72749169
• NM_000069.3:c.5570G>A

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.5570G>A​(p.Ser1857Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 1,612,148 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0034 (12 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 3.42
• Publications: 8 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=0.0077617764).
• BP6: Variant 1-201039883-C-T is Benign according to our data. Variant chr1-201039883-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00203 (309/152248) while in subpopulation NFE AF = 0.00368 (250/67988). AF 95% confidence interval is 0.0033. There are 1 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.5570G>A	p.Ser1857Asn	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.5570G>A	p.Ser1857Asn	missense	Exon 44 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.5513G>A	p.Ser1838Asn	missense	Exon 43 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.5510G>A	p.Ser1837Asn	missense	Exon 43 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 310 AN: 152130 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00369

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00211 AC: 528 AN: 250056 AF XY: 0.00217

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00117

Gnomad NFE exome AF: 0.00400

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00341 AC: 4983 AN: 1459900 Hom.: 12 Cov.: 31 AF XY: 0.00336 AC XY: 2438 AN XY: 726378

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.000671 AC: 30 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

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

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00128 AC: 66 AN: 51452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00424 AC: 4714 AN: 1111994

Other (OTH) AF: 0.00235 AC: 142 AN: 60388

GnomAD4 genome AF: 0.00203 AC: 309 AN: 152248 Hom.: 1 Cov.: 34 AF XY: 0.00191 AC XY: 142 AN XY: 74456

African (AFR) AF: 0.000433 AC: 18 AN: 41552

American (AMR) AF: 0.000719 AC: 11 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00368 AC: 250 AN: 67988

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00328 Hom.: 2

Bravo AF: 0.00198

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00187 AC: 227

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00456

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	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 of anesthesia (1)
-	-	1	Malignant hyperthermia, susceptibility to, 5;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1 (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	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0086	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.0078	T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.8	L
PhyloP100		3.4
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.61	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.36	T
Polyphen		0.079	B
Vest4		0.058
MVP		0.93
MPC		0.11
ClinPred		0.027	T
GERP RS		4.5
Varity_R		0.17
gMVP		0.24
Mutation Taster		=96/4	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: rs72749169; hg19: chr1-201009011; COSMIC: COSV99054152; COSMIC: COSV99054152;