chr1-201074499-C-A

Variant names:

• chr1-201074499-C-A
• rs79984703
• NM_000069.3:c.2063+7G>T

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.2063+7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,574,482 control chromosomes in the GnomAD database, including 858 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 0.024 (72 hom., cov: 34)
  • Exomes 𝑓: 0.029 (786 hom.)
• Consequence: CACNA1S NM_000069.3 splice_region, intron
• Scores: Splicing: ADA: 0.0004475
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.308
• Publications: 8 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=-0.7).
• BP6: Variant 1-201074499-C-A is Benign according to our data. Variant chr1-201074499-C-A is described in ClinVar as Benign. ClinVar VariationId is 254810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0238 (3623/152362) while in subpopulation NFE AF = 0.0319 (2169/68022). AF 95% confidence interval is 0.0308. There are 72 homozygotes in GnomAd4. There are 1888 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 72 AD,AR,SD 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.2063+7G>T		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.2063+7G>T		splice_region intron	N/A	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.2063+7G>T		splice_region intron	N/A	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.2063+7G>T		splice_region intron	N/A	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3629 AN: 152244 Hom.: 72 Cov.: 34

Gnomad AFR AF: 0.00646

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0225

Gnomad FIN AF: 0.0734

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0181

GnomAD2 exomes AF: 0.0257 AC: 6411 AN: 249350 AF XY: 0.0268

Gnomad AFR exome AF: 0.00561

Gnomad AMR exome AF: 0.00889

Gnomad ASJ exome AF: 0.00810

Gnomad EAS exome AF: 0.000382

Gnomad FIN exome AF: 0.0666

Gnomad NFE exome AF: 0.0315

Gnomad OTH exome AF: 0.0249

GnomAD4 exome AF: 0.0294 AC: 41831 AN: 1422120 Hom.: 786 Cov.: 27 AF XY: 0.0295 AC XY: 20943 AN XY: 709696

African (AFR) AF: 0.00652 AC: 213 AN: 32654

American (AMR) AF: 0.00906 AC: 404 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00843 AC: 218 AN: 25864

East Asian (EAS) AF: 0.000253 AC: 10 AN: 39498

South Asian (SAS) AF: 0.0274 AC: 2337 AN: 85162

European-Finnish (FIN) AF: 0.0632 AC: 3369 AN: 53288

Middle Eastern (MID) AF: 0.0241 AC: 137 AN: 5680

European-Non Finnish (NFE) AF: 0.0313 AC: 33662 AN: 1076244

Other (OTH) AF: 0.0250 AC: 1481 AN: 59124

GnomAD4 genome AF: 0.0238 AC: 3623 AN: 152362 Hom.: 72 Cov.: 34 AF XY: 0.0253 AC XY: 1888 AN XY: 74504

African (AFR) AF: 0.00644 AC: 268 AN: 41602

American (AMR) AF: 0.0102 AC: 156 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.0222 AC: 107 AN: 4830

European-Finnish (FIN) AF: 0.0734 AC: 780 AN: 10624

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0319 AC: 2169 AN: 68022

Other (OTH) AF: 0.0180 AC: 38 AN: 2116

Alfa AF: 0.0275 Hom.: 53

Bravo AF: 0.0186

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (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	Thyrotoxic periodic paralysis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.6
DANN	Benign	0.78
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00045
dbscSNV1_RF	Benign	0.032
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: rs79984703; hg19: chr1-201043627;