rs1998721

Variant names:

• chr1-201075620-A-G
• rs1998721
• NM_000069.3:c.1828-5T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000069.3(CACNA1S):​c.1828-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 1,613,192 control chromosomes in the GnomAD database, including 490,367 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40485 hom., cov: 33)
  • Exomes 𝑓: 0.78 (449882 hom.)
• Consequence: CACNA1S NM_000069.3 splice_region, intron
• Scores: Splicing: ADA: 0.00006350
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.512
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-201075620-A-G is Benign according to our data. Variant chr1-201075620-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.938 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.1828-5T>C		splice_region intron	N/A	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.1828-5T>C		splice_region intron	N/A	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.1828-5T>C		splice_region intron	N/A	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.1828-5T>C		splice_region intron	N/A	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109599 AN: 152054 Hom.: 40463 Cov.: 33

Gnomad AFR AF: 0.550

Gnomad AMI AF: 0.863

Gnomad AMR AF: 0.733

Gnomad ASJ AF: 0.786

Gnomad EAS AF: 0.961

Gnomad SAS AF: 0.898

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.776

Gnomad OTH AF: 0.708

GnomAD2 exomes AF: 0.782 AC: 196572 AN: 251416 AF XY: 0.792

Gnomad AFR exome AF: 0.546

Gnomad AMR exome AF: 0.720

Gnomad ASJ exome AF: 0.782

Gnomad EAS exome AF: 0.960

Gnomad FIN exome AF: 0.780

Gnomad NFE exome AF: 0.776

Gnomad OTH exome AF: 0.782

GnomAD4 exome AF: 0.782 AC: 1143172 AN: 1461020 Hom.: 449882 Cov.: 45 AF XY: 0.786 AC XY: 571534 AN XY: 726850

African (AFR) AF: 0.542 AC: 18141 AN: 33450

American (AMR) AF: 0.723 AC: 32353 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20426 AN: 26116

East Asian (EAS) AF: 0.965 AC: 38285 AN: 39690

South Asian (SAS) AF: 0.885 AC: 76359 AN: 86250

European-Finnish (FIN) AF: 0.781 AC: 41731 AN: 53418

Middle Eastern (MID) AF: 0.760 AC: 4380 AN: 5764

European-Non Finnish (NFE) AF: 0.778 AC: 864256 AN: 1111238

Other (OTH) AF: 0.782 AC: 47241 AN: 60376

GnomAD4 genome AF: 0.721 AC: 109666 AN: 152172 Hom.: 40485 Cov.: 33 AF XY: 0.725 AC XY: 53961 AN XY: 74402

African (AFR) AF: 0.550 AC: 22809 AN: 41494

American (AMR) AF: 0.733 AC: 11216 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.786 AC: 2729 AN: 3472

East Asian (EAS) AF: 0.961 AC: 4974 AN: 5178

South Asian (SAS) AF: 0.899 AC: 4335 AN: 4824

European-Finnish (FIN) AF: 0.788 AC: 8342 AN: 10592

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.776 AC: 52764 AN: 67996

Other (OTH) AF: 0.712 AC: 1505 AN: 2114

Alfa AF: 0.756 Hom.: 45807

Bravo AF: 0.708

Asia WGS AF: 0.915 AC: 3179 AN: 3478

EpiCase AF: 0.767

EpiControl AF: 0.767

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Hypokalemic periodic paralysis, type 1 (2)
-	-	2	not provided (2)
-	-	1	Malignant hyperthermia, susceptibility to, 5 (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.36
DANN	Benign	0.42
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000063
dbscSNV1_RF	Benign	0.0020
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: rs1998721; hg19: chr1-201044748;