19-13207011-T-C

Position:

• chr19-13207011-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127222.2(CACNA1A):​c.*302A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00746 in 154,954 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (4 hom., cov: 26)
  • Exomes 𝑓: 0.0078 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.38

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 19-13207011-T-C is Benign according to our data. Variant chr19-13207011-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1211720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00742 (1024/138080) while in subpopulation NFE AF= 0.0102 (662/65060). AF 95% confidence interval is 0.00953. There are 4 homozygotes in gnomad4. There are 497 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1024 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.*302A>G		3_prime_UTR_variant	47/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.*302A>G		3_prime_UTR_variant	47/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.00742 AC: 1024 AN: 137992 Hom.: 4 Cov.: 26

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00115

Gnomad AMR AF: 0.00677

Gnomad ASJ AF: 0.00624

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00177

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00677

GnomAD4 exome AF: 0.00782 AC: 132 AN: 16874 Hom.: 0 Cov.: 0 AF XY: 0.00850 AC XY: 76 AN XY: 8944

Gnomad4 AFR exome AF: 0.00226

Gnomad4 AMR exome AF: 0.00813

Gnomad4 ASJ exome AF: 0.00469

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00163

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.00844

Gnomad4 OTH exome AF: 0.00987

GnomAD4 genome AF: 0.00742 AC: 1024 AN: 138080 Hom.: 4 Cov.: 26 AF XY: 0.00750 AC XY: 497 AN XY: 66266

Gnomad4 AFR AF: 0.00133

Gnomad4 AMR AF: 0.00676

Gnomad4 ASJ AF: 0.00624

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00177

Gnomad4 FIN AF: 0.0228

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.00672

Alfa AF: 0.00731 Hom.: 0

Bravo AF: 0.00628

Asia WGS AF: 0.00202 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.88

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: rs111240372; hg19: chr19-13317825;