NM_000069.3:c.3953+66G>C

Variant names:

• chr1-201052491-C-G
• rs12029212
• NM_000069.3:c.3953+66G>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.3953+66G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,282,898 control chromosomes in the GnomAD database, including 32,129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (9981 hom., cov: 31)
  • Exomes 𝑓: 0.18 (22148 hom.)
• Consequence: CACNA1S NM_000069.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.975
• Publications: 10 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=-0.88).
• BP6: Variant 1-201052491-C-G is Benign according to our data. Variant chr1-201052491-C-G is described in ClinVar as Benign. ClinVar VariationId is 678226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.619 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	NM_000069.3	MANE Select	c.3953+66G>C		intron	N/A	NP_000060.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	ENST00000362061.4	TSL:1 MANE Select	c.3953+66G>C		intron	N/A	ENSP00000355192.3
	CACNA1S	ENST00000367338.7	TSL:5	c.3896+66G>C		intron	N/A	ENSP00000356307.3
	CACNA1S	ENST00000681874.1		c.3893+66G>C		intron	N/A	ENSP00000505162.1

Frequencies

GnomAD3 genomes AF: 0.298 AC: 44935 AN: 150860 Hom.: 9962 Cov.: 31

Gnomad AFR AF: 0.625

Gnomad AMI AF: 0.0759

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.0932

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.246

GnomAD4 exome AF: 0.181 AC: 204950 AN: 1131918 Hom.: 22148 AF XY: 0.176 AC XY: 102006 AN XY: 578332

African (AFR) AF: 0.640 AC: 17494 AN: 27334

American (AMR) AF: 0.118 AC: 5194 AN: 44068

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 4802 AN: 23786

East Asian (EAS) AF: 0.137 AC: 5144 AN: 37630

South Asian (SAS) AF: 0.101 AC: 8072 AN: 79554

European-Finnish (FIN) AF: 0.191 AC: 10078 AN: 52644

Middle Eastern (MID) AF: 0.196 AC: 828 AN: 4222

European-Non Finnish (NFE) AF: 0.176 AC: 143159 AN: 813506

Other (OTH) AF: 0.207 AC: 10179 AN: 49174

GnomAD4 genome AF: 0.298 AC: 44997 AN: 150980 Hom.: 9981 Cov.: 31 AF XY: 0.292 AC XY: 21574 AN XY: 73776

African (AFR) AF: 0.626 AC: 25856 AN: 41332

American (AMR) AF: 0.185 AC: 2815 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 680 AN: 3450

East Asian (EAS) AF: 0.134 AC: 681 AN: 5072

South Asian (SAS) AF: 0.0929 AC: 441 AN: 4748

European-Finnish (FIN) AF: 0.205 AC: 2091 AN: 10198

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11807 AN: 67688

Other (OTH) AF: 0.242 AC: 506 AN: 2090

Alfa AF: 0.0979 Hom.: 127

Bravo AF: 0.313

Asia WGS AF: 0.143 AC: 499 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.0
DANN	Benign	0.47
PhyloP100		0.97
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: rs12029212; hg19: chr1-201021619;