chr19-13529121-G-C

Position:

• chr19-13529121-G-C

Variant summary

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

The ENST00000592864.3(CACNA1A):​c.195-9618C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,064 control chromosomes in the GnomAD database, including 2,476 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 0.16 (2476 hom., cov: 32)
• Consequence: CACNA1A ENST00000592864.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.13529121G>C		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000664864.1	c.195-22896C>G		intron_variant				ENSP00000499449.1
CACNA1A	ENST00000592864.3	c.195-9618C>G		intron_variant		3		ENSP00000464729.2
CACNA1A	ENST00000574974.3	n.194+70632C>G		intron_variant		5		ENSP00000459963.3

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24095 AN: 151946 Hom.: 2477 Cov.: 32

Gnomad AFR AF: 0.0387

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.135

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.158 AC: 24091 AN: 152064 Hom.: 2476 Cov.: 32 AF XY: 0.163 AC XY: 12084 AN XY: 74326

Gnomad4 AFR AF: 0.0386

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.301

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.134

Alfa AF: 0.0993 Hom.: 187

Bravo AF: 0.143

Asia WGS AF: 0.117 AC: 411 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.90

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12975717; hg19: chr19-13639935;