chr1-201077934-G-A

Variant names:

• chr1-201077934-G-A
• rs4915476
• NM_000069.3:c.1564C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000069.3(CACNA1S):​c.1564C>T​(p.Leu522Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.215 in 1,613,632 control chromosomes in the GnomAD database, including 39,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4049 hom., cov: 33)
  • Exomes 𝑓: 0.21 (35189 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.91
• Publications: 18 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 1-201077934-G-A is Benign according to our data. Variant chr1-201077934-G-A is described in ClinVar as Benign. ClinVar VariationId is 254801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.255 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.1564C>T	p.Leu522Leu	synonymous	Exon 11 of 44	NP_000060.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	ENST00000362061.4	TSL:1 MANE Select	c.1564C>T	p.Leu522Leu	synonymous	Exon 11 of 44	ENSP00000355192.3
	CACNA1S	ENST00000367338.7	TSL:5	c.1564C>T	p.Leu522Leu	synonymous	Exon 11 of 43	ENSP00000356307.3
	CACNA1S	ENST00000681874.1		c.1564C>T	p.Leu522Leu	synonymous	Exon 11 of 43	ENSP00000505162.1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34218 AN: 152086 Hom.: 4045 Cov.: 33

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.0402

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.263

GnomAD2 exomes AF: 0.209 AC: 52602 AN: 251284 AF XY: 0.205

Gnomad AFR exome AF: 0.259

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.0403

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.229

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.214 AC: 313111 AN: 1461428 Hom.: 35189 Cov.: 33 AF XY: 0.211 AC XY: 153600 AN XY: 727048

African (AFR) AF: 0.255 AC: 8548 AN: 33470

American (AMR) AF: 0.270 AC: 12063 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 5985 AN: 26132

East Asian (EAS) AF: 0.0363 AC: 1440 AN: 39688

South Asian (SAS) AF: 0.113 AC: 9717 AN: 86250

European-Finnish (FIN) AF: 0.236 AC: 12630 AN: 53420

Middle Eastern (MID) AF: 0.243 AC: 1404 AN: 5766

European-Non Finnish (NFE) AF: 0.224 AC: 248763 AN: 1111608

Other (OTH) AF: 0.208 AC: 12561 AN: 60376

GnomAD4 genome AF: 0.225 AC: 34246 AN: 152204 Hom.: 4049 Cov.: 33 AF XY: 0.221 AC XY: 16476 AN XY: 74424

African (AFR) AF: 0.259 AC: 10770 AN: 41516

American (AMR) AF: 0.248 AC: 3798 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 768 AN: 3470

East Asian (EAS) AF: 0.0403 AC: 209 AN: 5192

South Asian (SAS) AF: 0.0998 AC: 481 AN: 4820

European-Finnish (FIN) AF: 0.217 AC: 2304 AN: 10602

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.221 AC: 15025 AN: 67994

Other (OTH) AF: 0.260 AC: 549 AN: 2112

Alfa AF: 0.195 Hom.: 1236

Bravo AF: 0.232

Asia WGS AF: 0.0740 AC: 258 AN: 3478

EpiCase AF: 0.238

EpiControl AF: 0.247

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Hypokalemic periodic paralysis, type 1 (2)
-	-	2	Malignant hyperthermia, susceptibility to, 5 (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
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.7
DANN	Benign	0.75
PhyloP100		4.9
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: rs4915476; hg19: chr1-201047062; COSMIC: COSV62944479;