chr19-13212945-A-G

Position:

• chr19-13212945-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127222.2(CACNA1A):​c.5941-205T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.773 in 151,850 control chromosomes in the GnomAD database, including 45,565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.77 (45565 hom., cov: 30)
• Consequence: CACNA1A NM_001127222.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.404

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]

CACNA1A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-13212945-A-G is Benign according to our data. Variant chr19-13212945-A-G is described in ClinVar as [Benign]. Clinvar id is 1192597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5941-205T>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.5941-205T>C		intron_variant		1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5959-205T>C		intron_variant		5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5947-205T>C		intron_variant		5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5944-205T>C		intron_variant		5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5944-205T>C		intron_variant		1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5944-205T>C		intron_variant		5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5803-205T>C		intron_variant		5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5944-205T>C		intron_variant		5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5959-205T>C		intron_variant		5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5950-205T>C		intron_variant		5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5947-205T>C		intron_variant		5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5944-205T>C		intron_variant		5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5944-205T>C		intron_variant		1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5944-205T>C		intron_variant		5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*243-205T>C		intron_variant		5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.773 AC: 117281 AN: 151732 Hom.: 45516 Cov.: 30

Gnomad AFR AF: 0.784

Gnomad AMI AF: 0.692

Gnomad AMR AF: 0.806

Gnomad ASJ AF: 0.781

Gnomad EAS AF: 0.987

Gnomad SAS AF: 0.814

Gnomad FIN AF: 0.798

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.763

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

GnomAD4 genome AF: 0.773 AC: 117393 AN: 151850 Hom.: 45565 Cov.: 30 AF XY: 0.779 AC XY: 57818 AN XY: 74196

Gnomad4 AFR AF: 0.784

Gnomad4 AMR AF: 0.806

Gnomad4 ASJ AF: 0.781

Gnomad4 EAS AF: 0.987

Gnomad4 SAS AF: 0.815

Gnomad4 FIN AF: 0.798

Gnomad4 NFE AF: 0.736

Gnomad4 OTH AF: 0.764

Alfa AF: 0.744 Hom.: 55391

Bravo AF: 0.772

Asia WGS AF: 0.904 AC: 3143 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	- -

Spinocerebellar ataxia type 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Episodic ataxia type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Migraine, familial hemiplegic, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Developmental and epileptic encephalopathy, 42 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.8
DANN	Benign	0.68

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: rs2419233; hg19: chr19-13323759;