1-201075485-G-C

Variant names:

• chr1-201075485-G-C
• rs201173419
• NM_000069.3:c.1948+10C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000069.3(CACNA1S):​c.1948+10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,509,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: CACNA1S NM_000069.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.55
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-201075485-G-C is Benign according to our data. Variant chr1-201075485-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254805.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 = 0.00096 (131/136438) while in subpopulation NFE AF = 0.000975 (64/65636). AF 95% confidence interval is 0.000783. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

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.1948+10C>G		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.1948+10C>G		intron	N/A	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.1948+10C>G		intron	N/A	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.1948+10C>G		intron	N/A	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.000960 AC: 131 AN: 136394 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000499

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00431

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000975

Gnomad OTH AF: 0.00270

GnomAD2 exomes AF: 0.000570 AC: 143 AN: 250964 AF XY: 0.000538

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.000783

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00117 AC: 1605 AN: 1372982 Hom.: 0 Cov.: 39 AF XY: 0.00111 AC XY: 761 AN XY: 683276

African (AFR) AF: 0.000289 AC: 9 AN: 31168

American (AMR) AF: 0.000303 AC: 13 AN: 42902

Ashkenazi Jewish (ASJ) AF: 0.000630 AC: 15 AN: 23806

East Asian (EAS) AF: 0.0000847 AC: 3 AN: 35408

South Asian (SAS) AF: 0.00 AC: 0 AN: 84414

European-Finnish (FIN) AF: 0.00127 AC: 61 AN: 48178

Middle Eastern (MID) AF: 0.000186 AC: 1 AN: 5382

European-Non Finnish (NFE) AF: 0.00138 AC: 1445 AN: 1046118

Other (OTH) AF: 0.00104 AC: 58 AN: 55606

GnomAD4 genome AF: 0.000960 AC: 131 AN: 136438 Hom.: 0 Cov.: 30 AF XY: 0.00110 AC XY: 72 AN XY: 65230

African (AFR) AF: 0.000483 AC: 17 AN: 35174

American (AMR) AF: 0.000499 AC: 6 AN: 12034

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 4 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 4658

South Asian (SAS) AF: 0.00 AC: 0 AN: 4394

European-Finnish (FIN) AF: 0.00431 AC: 35 AN: 8130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.000975 AC: 64 AN: 65636

Other (OTH) AF: 0.00268 AC: 5 AN: 1868

Alfa AF: 0.000171 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hypokalemic periodic paralysis, type 1 (2)
-	-	2	not specified (2)
-	-	1	Congenital myopathy 18 (1)
-	-	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)
-	-	1	Thyrotoxic periodic paralysis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.028
DANN	Benign	0.37
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201173419; hg19: chr1-201044613;