19-13207094-T-G

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.*219A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 405,924 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (69 hom., cov: 27)
  • Exomes 𝑓: 0.010 (66 hom.)
• Consequence: CACNA1A NM_001127222.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.214

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=-0.93).
• BP6: Variant 19-13207094-T-G is Benign according to our data. Variant chr19-13207094-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 1208972.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.*219A>C		3_prime_UTR_variant	47/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.*219A>C		3_prime_UTR_variant	47/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2814 AN: 151404 Hom.: 69 Cov.: 27

Gnomad AFR AF: 0.0468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00631

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0664

Gnomad SAS AF: 0.0535

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000663

Gnomad OTH AF: 0.0116

GnomAD4 exome AF: 0.0100 AC: 2556 AN: 254410 Hom.: 66 Cov.: 4 AF XY: 0.0110 AC XY: 1477 AN XY: 134698

Gnomad4 AFR exome AF: 0.0444

Gnomad4 AMR exome AF: 0.00602

Gnomad4 ASJ exome AF: 0.000915

Gnomad4 EAS exome AF: 0.0595

Gnomad4 SAS exome AF: 0.0341

Gnomad4 FIN exome AF: 0.00990

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.0187 AC: 2829 AN: 151514 Hom.: 69 Cov.: 27 AF XY: 0.0194 AC XY: 1440 AN XY: 74058

Gnomad4 AFR AF: 0.0471

Gnomad4 AMR AF: 0.00630

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.0665

Gnomad4 SAS AF: 0.0538

Gnomad4 FIN AF: 0.0109

Gnomad4 NFE AF: 0.000664

Gnomad4 OTH AF: 0.0115

Alfa AF: 0.000862 Hom.: 2

Bravo AF: 0.0187

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.63
Dann	Benign	0.56

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: rs116023034; hg19: chr19-13317908;