1-201039521-T-A

Variant names:

• chr1-201039521-T-A
• rs190783634
• NM_000069.3:c.*310A>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.*310A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 476,440 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (4 hom., cov: 34)
  • Exomes 𝑓: 0.00061 (1 hom.)
• Consequence: CACNA1S NM_000069.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.437
• 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

ENSG00000234132 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-201039521-T-A is Benign according to our data. Variant chr1-201039521-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 294697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00469 (714/152348) while in subpopulation AFR AF = 0.0165 (687/41578). AF 95% confidence interval is 0.0155. There are 4 homozygotes in GnomAd4. There are 349 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 SD,AD,AR 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.*310A>T		3_prime_UTR	Exon 44 of 44	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.*310A>T		3_prime_UTR	Exon 44 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.*310A>T		3_prime_UTR	Exon 43 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.*310A>T		3_prime_UTR	Exon 43 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 712 AN: 152228 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.000614 AC: 199 AN: 324092 Hom.: 1 Cov.: 0 AF XY: 0.000553 AC XY: 94 AN XY: 169960

African (AFR) AF: 0.0159 AC: 156 AN: 9800

American (AMR) AF: 0.000763 AC: 10 AN: 13112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10226

East Asian (EAS) AF: 0.00 AC: 0 AN: 20430

South Asian (SAS) AF: 0.0000784 AC: 3 AN: 38270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18638

Middle Eastern (MID) AF: 0.000709 AC: 1 AN: 1410

European-Non Finnish (NFE) AF: 0.00000517 AC: 1 AN: 193516

Other (OTH) AF: 0.00150 AC: 28 AN: 18690

GnomAD4 genome AF: 0.00469 AC: 714 AN: 152348 Hom.: 4 Cov.: 34 AF XY: 0.00468 AC XY: 349 AN XY: 74512

African (AFR) AF: 0.0165 AC: 687 AN: 41578

American (AMR) AF: 0.00111 AC: 17 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00437 Hom.: 0

Bravo AF: 0.00528

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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)
-	-	1	Congenital myopathy 18 (1)
-	-	1	Malignant hyperthermia, susceptibility to, 5 (1)
-	-	1	not provided (1)
-	-	1	Thyrotoxic periodic paralysis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.0
DANN	Benign	0.90
PhyloP100		0.44
Mutation Taster		=100/0	polymorphism

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: rs190783634; hg19: chr1-201008649;