NM_000069.3:c.1551T>C

Variant names:

• chr1-201077947-A-G
• rs4915477
• NM_000069.3:c.1551T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000069.3(CACNA1S):​c.1551T>C​(p.Gly517Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 1,613,174 control chromosomes in the GnomAD database, including 337,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (37788 hom., cov: 33)
  • Exomes 𝑓: 0.63 (299855 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.15
• Publications: 23 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-201077947-A-G is Benign according to our data. Variant chr1-201077947-A-G is described in ClinVar as Benign. ClinVar VariationId is 254800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.885 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.1551T>C	p.Gly517Gly	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.1551T>C	p.Gly517Gly	synonymous	Exon 11 of 44	ENSP00000355192.3
	CACNA1S	ENST00000367338.7	TSL:5	c.1551T>C	p.Gly517Gly	synonymous	Exon 11 of 43	ENSP00000356307.3
	CACNA1S	ENST00000681874.1		c.1551T>C	p.Gly517Gly	synonymous	Exon 11 of 43	ENSP00000505162.1

Frequencies

GnomAD3 genomes AF: 0.685 AC: 104086 AN: 152006 Hom.: 37747 Cov.: 33

Gnomad AFR AF: 0.893

Gnomad AMI AF: 0.689

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.712

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.690

GnomAD2 exomes AF: 0.579 AC: 145567 AN: 251274 AF XY: 0.567

Gnomad AFR exome AF: 0.896

Gnomad AMR exome AF: 0.586

Gnomad ASJ exome AF: 0.706

Gnomad EAS exome AF: 0.225

Gnomad FIN exome AF: 0.534

Gnomad NFE exome AF: 0.654

Gnomad OTH exome AF: 0.611

GnomAD4 exome AF: 0.630 AC: 919893 AN: 1461050 Hom.: 299855 Cov.: 48 AF XY: 0.620 AC XY: 450324 AN XY: 726856

African (AFR) AF: 0.903 AC: 30232 AN: 33474

American (AMR) AF: 0.590 AC: 26367 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.712 AC: 18608 AN: 26130

East Asian (EAS) AF: 0.256 AC: 10171 AN: 39680

South Asian (SAS) AF: 0.321 AC: 27662 AN: 86240

European-Finnish (FIN) AF: 0.545 AC: 29107 AN: 53418

Middle Eastern (MID) AF: 0.664 AC: 3831 AN: 5766

European-Non Finnish (NFE) AF: 0.663 AC: 736271 AN: 1111270

Other (OTH) AF: 0.624 AC: 37644 AN: 60354

GnomAD4 genome AF: 0.685 AC: 104183 AN: 152124 Hom.: 37788 Cov.: 33 AF XY: 0.668 AC XY: 49693 AN XY: 74366

African (AFR) AF: 0.893 AC: 37085 AN: 41524

American (AMR) AF: 0.651 AC: 9949 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.712 AC: 2468 AN: 3468

East Asian (EAS) AF: 0.234 AC: 1210 AN: 5162

South Asian (SAS) AF: 0.295 AC: 1422 AN: 4816

European-Finnish (FIN) AF: 0.522 AC: 5529 AN: 10588

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.651 AC: 44222 AN: 67972

Other (OTH) AF: 0.689 AC: 1455 AN: 2112

Alfa AF: 0.681 Hom.: 59945

Bravo AF: 0.710

Asia WGS AF: 0.302 AC: 1057 AN: 3478

EpiCase AF: 0.661

EpiControl AF: 0.677

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Hypokalemic periodic paralysis, type 1 (2)
-	-	1	Malignant hyperthermia, susceptibility to, 5 (1)
-	-	1	Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.90
DANN	Benign	0.60
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs4915477; hg19: chr1-201047075; COSMIC: COSV62938741;