rs56021911

Variant names:

• chr1-201059171-G-A
• rs56021911
• NM_000069.3:c.3525+18C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-201059171-G-A
• chr1-201059171-G-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.3525+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,535,186 control chromosomes in the GnomAD database, including 355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (26 hom., cov: 33)
  • Exomes 𝑓: 0.020 (329 hom.)
• Consequence: CACNA1S NM_000069.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.277
• Publications: 4 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=-0.92).
• BP6: Variant 1-201059171-G-A is Benign according to our data. Variant chr1-201059171-G-A is described in ClinVar as Benign. ClinVar VariationId is 254826.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 = 0.0151 (2307/152284) while in subpopulation NFE AF = 0.0227 (1542/68026). AF 95% confidence interval is 0.0217. There are 26 homozygotes in GnomAd4. There are 1147 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 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.3525+18C>T		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.3525+18C>T		intron	N/A	ENSP00000355192.3
	CACNA1S	ENST00000367338.7	TSL:5	c.3525+18C>T		intron	N/A	ENSP00000356307.3
	CACNA1S	ENST00000681874.1		c.3465+18C>T		intron	N/A	ENSP00000505162.1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2308 AN: 152166 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00910

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0330

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0145 AC: 3630 AN: 250114 AF XY: 0.0146

Gnomad AFR exome AF: 0.00297

Gnomad AMR exome AF: 0.00548

Gnomad ASJ exome AF: 0.00676

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.0300

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0203 AC: 28125 AN: 1382902 Hom.: 329 Cov.: 24 AF XY: 0.0199 AC XY: 13751 AN XY: 692292

African (AFR) AF: 0.00285 AC: 91 AN: 31882

American (AMR) AF: 0.00597 AC: 266 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00917 AC: 235 AN: 25640

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39346

South Asian (SAS) AF: 0.00197 AC: 166 AN: 84448

European-Finnish (FIN) AF: 0.0300 AC: 1599 AN: 53244

Middle Eastern (MID) AF: 0.000184 AC: 1 AN: 5442

European-Non Finnish (NFE) AF: 0.0238 AC: 24736 AN: 1040536

Other (OTH) AF: 0.0178 AC: 1030 AN: 57808

GnomAD4 genome AF: 0.0151 AC: 2307 AN: 152284 Hom.: 26 Cov.: 33 AF XY: 0.0154 AC XY: 1147 AN XY: 74460

African (AFR) AF: 0.00455 AC: 189 AN: 41562

American (AMR) AF: 0.00902 AC: 138 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00835 AC: 29 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.0330 AC: 350 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0227 AC: 1542 AN: 68026

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.0172 Hom.: 7

Bravo AF: 0.0132

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Congenital myopathy 18 (1)
-	-	1	Hypokalemic periodic paralysis, type 1 (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	0.66
DANN	Benign	0.60
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs56021911; hg19: chr1-201028299;