19-13207166-G-T

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.*147C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 896,776 control chromosomes in the GnomAD database, including 90,744 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.48 (17903 hom., cov: 29)
  • Exomes 𝑓: 0.44 (72841 hom.)
• Consequence: CACNA1A NM_001127222.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0930

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=-0.71).
• BP6: Variant 19-13207166-G-T is Benign according to our data. Variant chr19-13207166-G-T is described in ClinVar as [Benign]. Clinvar id is 1292948.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.*147C>A		3_prime_UTR_variant	47/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.*147C>A		3_prime_UTR_variant	47/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.480 AC: 72581 AN: 151216 Hom.: 17877 Cov.: 29

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.585

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.641

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.519

GnomAD4 exome AF: 0.437 AC: 325472 AN: 745448 Hom.: 72841 Cov.: 10 AF XY: 0.443 AC XY: 166138 AN XY: 375138

Gnomad4 AFR exome AF: 0.585

Gnomad4 AMR exome AF: 0.535

Gnomad4 ASJ exome AF: 0.525

Gnomad4 EAS exome AF: 0.352

Gnomad4 SAS exome AF: 0.590

Gnomad4 FIN exome AF: 0.409

Gnomad4 NFE exome AF: 0.419

Gnomad4 OTH exome AF: 0.461

GnomAD4 genome AF: 0.480 AC: 72659 AN: 151328 Hom.: 17903 Cov.: 29 AF XY: 0.482 AC XY: 35633 AN XY: 73972

Gnomad4 AFR AF: 0.574

Gnomad4 AMR AF: 0.507

Gnomad4 ASJ AF: 0.530

Gnomad4 EAS AF: 0.369

Gnomad4 SAS AF: 0.584

Gnomad4 FIN AF: 0.418

Gnomad4 NFE AF: 0.424

Gnomad4 OTH AF: 0.525

Alfa AF: 0.449 Hom.: 12986

Bravo AF: 0.489

Asia WGS AF: 0.552 AC: 1915 AN: 3470

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 14, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	1.7
Dann	Benign	0.91

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: rs7254351; hg19: chr19-13317980; COSMIC: COSV64207533; COSMIC: COSV64207533;