1-201047518-C-T

Variant names:

• chr1-201047518-C-T
• rs2297905
• NM_000069.3:c.4543+7G>A

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.4543+7G>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 0.132 in 1,607,216 control chromosomes in the GnomAD database, including 16,484 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3453 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13031 hom.)
• Consequence: CACNA1S NM_000069.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002208
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.367
• 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):

• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-201047518-C-T is Benign according to our data. Variant chr1-201047518-C-T is described in ClinVar as Benign. ClinVar VariationId is 254838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.345 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.4543+7G>A		splice_region intron	N/A	NP_000060.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	ENST00000362061.4	TSL:1 MANE Select	c.4543+7G>A		splice_region intron	N/A	ENSP00000355192.3
	CACNA1S	ENST00000367338.7	TSL:5	c.4486+7G>A		splice_region intron	N/A	ENSP00000356307.3
	CACNA1S	ENST00000681874.1		c.4483+7G>A		splice_region intron	N/A	ENSP00000505162.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28224 AN: 152040 Hom.: 3446 Cov.: 33

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.0948

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.0613

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.159

GnomAD2 exomes AF: 0.127 AC: 31937 AN: 251082 AF XY: 0.121

Gnomad AFR exome AF: 0.359

Gnomad AMR exome AF: 0.0733

Gnomad ASJ exome AF: 0.0991

Gnomad EAS exome AF: 0.133

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.127 AC: 184448 AN: 1455058 Hom.: 13031 Cov.: 30 AF XY: 0.124 AC XY: 90034 AN XY: 724256

African (AFR) AF: 0.357 AC: 11893 AN: 33272

American (AMR) AF: 0.0790 AC: 3529 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0989 AC: 2582 AN: 26104

East Asian (EAS) AF: 0.127 AC: 5056 AN: 39660

South Asian (SAS) AF: 0.0649 AC: 5593 AN: 86118

European-Finnish (FIN) AF: 0.139 AC: 7401 AN: 53398

Middle Eastern (MID) AF: 0.106 AC: 608 AN: 5744

European-Non Finnish (NFE) AF: 0.126 AC: 139572 AN: 1105884

Other (OTH) AF: 0.136 AC: 8214 AN: 60180

GnomAD4 genome AF: 0.186 AC: 28256 AN: 152158 Hom.: 3453 Cov.: 33 AF XY: 0.182 AC XY: 13548 AN XY: 74406

African (AFR) AF: 0.350 AC: 14510 AN: 41472

American (AMR) AF: 0.132 AC: 2015 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0948 AC: 329 AN: 3470

East Asian (EAS) AF: 0.126 AC: 655 AN: 5184

South Asian (SAS) AF: 0.0609 AC: 294 AN: 4826

European-Finnish (FIN) AF: 0.146 AC: 1547 AN: 10592

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8531 AN: 68006

Other (OTH) AF: 0.156 AC: 329 AN: 2106

Alfa AF: 0.146 Hom.: 6434

Bravo AF: 0.195

Asia WGS AF: 0.115 AC: 398 AN: 3478

EpiCase AF: 0.119

EpiControl AF: 0.122

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Hypokalemic periodic paralysis, type 1 (2)
-	-	1	Congenital myopathy 18 (1)
-	-	1	Malignant hyperthermia, susceptibility to, 5 (1)
-	-	1	Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 (1)
-	-	1	not provided (1)
-	-	1	Thyrotoxic periodic paralysis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.55
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
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: rs2297905; hg19: chr1-201016646; COSMIC: COSV107453946; COSMIC: COSV107453946;