rs9427714

Variant names:

• chr1-201077983-A-G
• rs9427714
• NM_000069.3:c.1515T>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.1515T>C​(p.Cys505Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,613,586 control chromosomes in the GnomAD database, including 94,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5892 hom., cov: 32)
  • Exomes 𝑓: 0.33 (88880 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.211
• Publications: 16 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 1-201077983-A-G is Benign according to our data. Variant chr1-201077983-A-G is described in ClinVar as Benign. ClinVar VariationId is 254797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.211 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.367 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.1515T>C	p.Cys505Cys	synonymous	Exon 11 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.1515T>C	p.Cys505Cys	synonymous	Exon 11 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.1515T>C	p.Cys505Cys	synonymous	Exon 11 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.1515T>C	p.Cys505Cys	synonymous	Exon 11 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36618 AN: 152168 Hom.: 5887 Cov.: 32

Gnomad AFR AF: 0.0749

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.000960

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.241 AC: 60598 AN: 251416 AF XY: 0.246

Gnomad AFR exome AF: 0.0668

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.362

Gnomad OTH exome AF: 0.273

GnomAD4 exome AF: 0.332 AC: 484628 AN: 1461300 Hom.: 88880 Cov.: 41 AF XY: 0.327 AC XY: 237509 AN XY: 726986

African (AFR) AF: 0.0629 AC: 2104 AN: 33476

American (AMR) AF: 0.148 AC: 6607 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 7978 AN: 26136

East Asian (EAS) AF: 0.000706 AC: 28 AN: 39684

South Asian (SAS) AF: 0.143 AC: 12344 AN: 86246

European-Finnish (FIN) AF: 0.214 AC: 11415 AN: 53418

Middle Eastern (MID) AF: 0.217 AC: 1251 AN: 5768

European-Non Finnish (NFE) AF: 0.382 AC: 424857 AN: 1111478

Other (OTH) AF: 0.299 AC: 18044 AN: 60372

GnomAD4 genome AF: 0.241 AC: 36631 AN: 152286 Hom.: 5892 Cov.: 32 AF XY: 0.229 AC XY: 17032 AN XY: 74462

African (AFR) AF: 0.0752 AC: 3124 AN: 41564

American (AMR) AF: 0.231 AC: 3542 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1077 AN: 3470

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5194

South Asian (SAS) AF: 0.133 AC: 642 AN: 4832

European-Finnish (FIN) AF: 0.204 AC: 2161 AN: 10594

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.371 AC: 25216 AN: 68006

Other (OTH) AF: 0.232 AC: 490 AN: 2114

Alfa AF: 0.306 Hom.: 8647

Bravo AF: 0.234

Asia WGS AF: 0.0820 AC: 289 AN: 3478

EpiCase AF: 0.355

EpiControl AF: 0.361

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.72
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs9427714; hg19: chr1-201047111;