rs1546416

Variant names:

• chr1-201040428-A-G
• rs1546416
• NM_000069.3:c.5227-54T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-201040428-A-G
• chr1-201040428-A-T

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.5227-54T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,602,084 control chromosomes in the GnomAD database, including 98,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10014 hom., cov: 33)
  • Exomes 𝑓: 0.35 (88237 hom.)
• Consequence: CACNA1S NM_000069.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.347
• Publications: 15 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

ENSG00000234132 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-201040428-A-G is Benign according to our data. Variant chr1-201040428-A-G is described in ClinVar as Benign. ClinVar VariationId is 678243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.41 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.5227-54T>C		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.5227-54T>C		intron	N/A	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.5170-54T>C		intron	N/A	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.5167-54T>C		intron	N/A	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54438 AN: 152026 Hom.: 9989 Cov.: 33

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.336

GnomAD4 exome AF: 0.347 AC: 503038 AN: 1449940 Hom.: 88237 Cov.: 32 AF XY: 0.344 AC XY: 247925 AN XY: 721354

African (AFR) AF: 0.415 AC: 13859 AN: 33392

American (AMR) AF: 0.312 AC: 13773 AN: 44104

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 9501 AN: 25994

East Asian (EAS) AF: 0.285 AC: 11280 AN: 39628

South Asian (SAS) AF: 0.266 AC: 22811 AN: 85736

European-Finnish (FIN) AF: 0.323 AC: 15137 AN: 46874

Middle Eastern (MID) AF: 0.348 AC: 2008 AN: 5766

European-Non Finnish (NFE) AF: 0.355 AC: 393972 AN: 1108308

Other (OTH) AF: 0.344 AC: 20697 AN: 60138

GnomAD4 genome AF: 0.358 AC: 54508 AN: 152144 Hom.: 10014 Cov.: 33 AF XY: 0.355 AC XY: 26437 AN XY: 74368

African (AFR) AF: 0.416 AC: 17242 AN: 41494

American (AMR) AF: 0.294 AC: 4499 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1247 AN: 3470

East Asian (EAS) AF: 0.297 AC: 1538 AN: 5176

South Asian (SAS) AF: 0.262 AC: 1265 AN: 4824

European-Finnish (FIN) AF: 0.322 AC: 3411 AN: 10580

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 24014 AN: 67972

Other (OTH) AF: 0.342 AC: 722 AN: 2114

Alfa AF: 0.357 Hom.: 20296

Bravo AF: 0.361

Asia WGS AF: 0.308 AC: 1073 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hypokalemic periodic paralysis, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.90
DANN	Benign	0.53
PhyloP100		-0.35
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: rs1546416; hg19: chr1-201009556; COSMIC: COSV62945146; COSMIC: COSV62945146;