rs2074880

chr19-13261817-A-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.4090-207T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 553,396 control chromosomes in the GnomAD database, including 31,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.29 (7218 hom., cov: 32)
  • Exomes 𝑓: 0.34 (23845 hom.)
• Consequence: CACNA1A NM_001127222.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.369

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=-0.89).
• BP6: Variant 19-13261817-A-C is Benign according to our data. Variant chr19-13261817-A-C is described in ClinVar as [Benign]. Clinvar id is 678176.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.4090-207T>G		intron_variant		ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4090-207T>G		intron_variant		1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44821 AN: 152030 Hom.: 7224 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.312

GnomAD4 exome AF: 0.339 AC: 135992 AN: 401248 Hom.: 23845 Cov.: 4 AF XY: 0.338 AC XY: 70898 AN XY: 210032

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.232

Gnomad4 ASJ exome AF: 0.356

Gnomad4 EAS exome AF: 0.339

Gnomad4 SAS exome AF: 0.291

Gnomad4 FIN exome AF: 0.293

Gnomad4 NFE exome AF: 0.366

Gnomad4 OTH exome AF: 0.343

GnomAD4 genome AF: 0.294 AC: 44800 AN: 152148 Hom.: 7218 Cov.: 32 AF XY: 0.291 AC XY: 21631 AN XY: 74372

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.273

Gnomad4 ASJ AF: 0.355

Gnomad4 EAS AF: 0.387

Gnomad4 SAS AF: 0.278

Gnomad4 FIN AF: 0.274

Gnomad4 NFE AF: 0.366

Gnomad4 OTH AF: 0.307

Alfa AF: 0.308 Hom.: 1711

Bravo AF: 0.289

Asia WGS AF: 0.296 AC: 1030 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 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	1.0
Dann	Benign	0.51

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: rs2074880; hg19: chr19-13372631;