chr19-13451411-A-G

Position:

• chr19-13451411-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000360228.11(CACNA1A):​c.539+1465T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 152,150 control chromosomes in the GnomAD database, including 4,454 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (4454 hom., cov: 32)
  • Exomes 𝑓: 0.080 (0 hom.)
• Consequence: CACNA1A ENST00000360228.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.687

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.539+1465T>C		intron_variant		ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.539+1465T>C		intron_variant		1	NM_001127222.2	ENSP00000353362

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31121 AN: 151982 Hom.: 4434 Cov.: 32

Gnomad AFR AF: 0.367

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.0928

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.169

GnomAD4 exome AF: 0.0800 AC: 4 AN: 50 Hom.: 0 Cov.: 0 AF XY: 0.111 AC XY: 4 AN XY: 36

Gnomad4 ASJ exome AF: 0.00

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.0250

Gnomad4 OTH exome AF: 0.333

GnomAD4 genome AF: 0.205 AC: 31180 AN: 152100 Hom.: 4454 Cov.: 32 AF XY: 0.208 AC XY: 15498 AN XY: 74346

Gnomad4 AFR AF: 0.367

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.0928

Gnomad4 EAS AF: 0.515

Gnomad4 SAS AF: 0.210

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.173

Alfa AF: 0.124 Hom.: 771

Bravo AF: 0.213

Asia WGS AF: 0.354 AC: 1229 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.7
DANN	Benign	0.75

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: rs11882861; hg19: chr19-13562225;