19-13257217-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001127222.2(CACNA1A):c.4590+133A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 667,660 control chromosomes in the GnomAD database, including 278,449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.92 (64931 hom., cov: 31)
  • Exomes 𝑓: 0.91 (213518 hom.)
• Consequence: CACNA1A NM_001127222.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.39

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-13257217-T-C is Benign according to our data. Variant chr19-13257217-T-C is described in ClinVar as [Benign]. Clinvar id is 1292944.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.96 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.4590+133A>G		intron_variant		ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4590+133A>G		intron_variant		1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.923 AC: 140365 AN: 152150 Hom.: 64869 Cov.: 31

Gnomad AFR AF: 0.967

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.945

Gnomad ASJ AF: 0.912

Gnomad EAS AF: 0.983

Gnomad SAS AF: 0.900

Gnomad FIN AF: 0.910

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.893

Gnomad OTH AF: 0.927

GnomAD4 exome AF: 0.910 AC: 468791 AN: 515392 Hom.: 213518 Cov.: 7 AF XY: 0.908 AC XY: 245873 AN XY: 270798

Gnomad4 AFR exome AF: 0.968

Gnomad4 AMR exome AF: 0.953

Gnomad4 ASJ exome AF: 0.908

Gnomad4 EAS exome AF: 0.990

Gnomad4 SAS exome AF: 0.903

Gnomad4 FIN exome AF: 0.913

Gnomad4 NFE exome AF: 0.896

Gnomad4 OTH exome AF: 0.919

GnomAD4 genome AF: 0.923 AC: 140486 AN: 152268 Hom.: 64931 Cov.: 31 AF XY: 0.923 AC XY: 68688 AN XY: 74434

Gnomad4 AFR AF: 0.967

Gnomad4 AMR AF: 0.945

Gnomad4 ASJ AF: 0.912

Gnomad4 EAS AF: 0.983

Gnomad4 SAS AF: 0.901

Gnomad4 FIN AF: 0.910

Gnomad4 NFE AF: 0.893

Gnomad4 OTH AF: 0.927

Alfa AF: 0.903 Hom.: 42711

Bravo AF: 0.929

Asia WGS AF: 0.945 AC: 3288 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 25, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.033
Dann	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs4926242; hg19: chr19-13368031;