rs191758096

Variant names:

• chr1-201053456-C-T
• rs191758096
• NM_000069.3:c.3795+3G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000069.3(CACNA1S):​c.3795+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,614,124 control chromosomes in the GnomAD database, including 15 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 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (14 hom.)
• Consequence: CACNA1S NM_000069.3 splice_region, intron
• Scores: Splicing: ADA: 0.0003253
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.645
• Publications: 0 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=-0.48).
• BP6: Variant 1-201053456-C-T is Benign according to our data. Variant chr1-201053456-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00128 (195/152248) while in subpopulation SAS AF = 0.00538 (26/4830). AF 95% confidence interval is 0.00377. There are 1 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 SD,AD,AR gene

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.3795+3G>A		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.3795+3G>A		splice_region intron	N/A	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.3738+3G>A		splice_region intron	N/A	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.3735+3G>A		splice_region intron	N/A	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00198 AC: 497 AN: 251402 AF XY: 0.00225

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00764

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00171 AC: 2494 AN: 1461876 Hom.: 14 Cov.: 35 AF XY: 0.00187 AC XY: 1362 AN XY: 727242

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.00145 AC: 65 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 226 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00486 AC: 419 AN: 86258

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53410

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.00144 AC: 1596 AN: 1112004

Other (OTH) AF: 0.00243 AC: 147 AN: 60396

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74438

African (AFR) AF: 0.000289 AC: 12 AN: 41538

American (AMR) AF: 0.000980 AC: 15 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00538 AC: 26 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00147 AC: 100 AN: 68008

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00167 Hom.: 0

Bravo AF: 0.00141

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00302

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Hypokalemic periodic paralysis, type 1 (2)
-	-	2	Malignant hyperthermia, susceptibility to, 5 (2)
-	-	1	Congenital myopathy 18 (1)
-	-	1	Hypokalemic periodic paralysis (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	-0.48
CADD	Benign	15
DANN	Benign	0.88
PhyloP100		0.65
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00033
dbscSNV1_RF	Benign	0.050
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: rs191758096; hg19: chr1-201022584;