chr1-201053248-G-A

Variant names:

• chr1-201053248-G-A
• rs56183942
• NM_000069.3:c.3822C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000069.3(CACNA1S):​c.3822C>T​(p.Ile1274Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,614,218 control chromosomes in the GnomAD database, including 1,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (141 hom., cov: 32)
  • Exomes 𝑓: 0.020 (943 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.611
• Publications: 14 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 1-201053248-G-A is Benign according to our data. Variant chr1-201053248-G-A is described in ClinVar as Benign. ClinVar VariationId is 254831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.611 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 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.3822C>T	p.Ile1274Ile	synonymous	Exon 31 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.3822C>T	p.Ile1274Ile	synonymous	Exon 31 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.3765C>T	p.Ile1255Ile	synonymous	Exon 30 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.3762C>T	p.Ile1254Ile	synonymous	Exon 30 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3311 AN: 152236 Hom.: 137 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0382

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.0438

Gnomad FIN AF: 0.00593

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0320

GnomAD2 exomes AF: 0.0370 AC: 9299 AN: 251396 AF XY: 0.0353

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.0727

Gnomad ASJ exome AF: 0.0269

Gnomad EAS exome AF: 0.172

Gnomad FIN exome AF: 0.00776

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.0293

GnomAD4 exome AF: 0.0204 AC: 29863 AN: 1461864 Hom.: 943 Cov.: 34 AF XY: 0.0210 AC XY: 15238 AN XY: 727234

African (AFR) AF: 0.0140 AC: 468 AN: 33480

American (AMR) AF: 0.0705 AC: 3153 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 732 AN: 26136

East Asian (EAS) AF: 0.171 AC: 6808 AN: 39698

South Asian (SAS) AF: 0.0422 AC: 3642 AN: 86258

European-Finnish (FIN) AF: 0.00779 AC: 416 AN: 53404

Middle Eastern (MID) AF: 0.0423 AC: 244 AN: 5768

European-Non Finnish (NFE) AF: 0.0116 AC: 12851 AN: 1112004

Other (OTH) AF: 0.0256 AC: 1549 AN: 60394

GnomAD4 genome AF: 0.0219 AC: 3335 AN: 152354 Hom.: 141 Cov.: 32 AF XY: 0.0228 AC XY: 1701 AN XY: 74498

African (AFR) AF: 0.0128 AC: 533 AN: 41592

American (AMR) AF: 0.0382 AC: 584 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 81 AN: 3472

East Asian (EAS) AF: 0.175 AC: 904 AN: 5176

South Asian (SAS) AF: 0.0443 AC: 214 AN: 4832

European-Finnish (FIN) AF: 0.00593 AC: 63 AN: 10626

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0126 AC: 857 AN: 68030

Other (OTH) AF: 0.0388 AC: 82 AN: 2114

Alfa AF: 0.0180 Hom.: 27

Bravo AF: 0.0261

Asia WGS AF: 0.108 AC: 376 AN: 3478

ClinVar

ClinVar submissions

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)
-	-	2	not provided (2)
-	-	1	Congenital myopathy 18 (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
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Benign	0.92
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs56183942; hg19: chr1-201022376; COSMIC: COSV62937039;