19-13206769-G-A

Position:

• chr19-13206769-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001127222.2(CACNA1A):​c.*544C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00736 in 154,008 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0074 (11 hom., cov: 30)
  • Exomes 𝑓: 0.0030 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.38

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 19-13206769-G-A is Benign according to our data. Variant chr19-13206769-G-A is described in ClinVar as [Benign]. Clinvar id is 3233571.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00743 (1127/151680) while in subpopulation AMR AF= 0.0198 (301/15218). AF 95% confidence interval is 0.0179. There are 11 homozygotes in gnomad4. There are 585 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1127 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.*544C>T		3_prime_UTR_variant	47/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.*544C>T		3_prime_UTR_variant	47/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.00740 AC: 1122 AN: 151562 Hom.: 10 Cov.: 30

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00907

Gnomad SAS AF: 0.00996

Gnomad FIN AF: 0.00615

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00762

Gnomad OTH AF: 0.0101

GnomAD4 exome AF: 0.00301 AC: 7 AN: 2328 Hom.: 0 Cov.: 0 AF XY: 0.00503 AC XY: 6 AN XY: 1192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00515

GnomAD4 genome AF: 0.00743 AC: 1127 AN: 151680 Hom.: 11 Cov.: 30 AF XY: 0.00789 AC XY: 585 AN XY: 74150

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.0198

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00909

Gnomad4 SAS AF: 0.00976

Gnomad4 FIN AF: 0.00615

Gnomad4 NFE AF: 0.00762

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00868 Hom.: 2

Bravo AF: 0.00877

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 08, 2024

Variant summary: CACNA1A c.*1277C>T is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.0071 in 31218 control chromosomes in the gnomAD database, including 4 homozygotes, strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.*1277C>T in individuals affected with Early Infantile Epileptic Encephalopathy 42 or other CACNA1A-related disorders and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.77

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: rs141221917; hg19: chr19-13317583;