19-13259662-C-T

Variant names:

• chr19-13259662-C-T
• rs555959123
• NM_001127222.2:c.4290G>A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001127222.2(CACNA1A):​c.4290G>A​(p.Ala1430Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,610,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.47

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 19-13259662-C-T is Benign according to our data. Variant chr19-13259662-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 542839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13259662-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-5.47 with no splicing effect.
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4290G>A	p.Ala1430Ala	synonymous_variant	Exon 27 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4290G>A	p.Ala1430Ala	synonymous_variant	Exon 27 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4302G>A	p.Ala1434Ala	synonymous_variant	Exon 27 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4296G>A	p.Ala1432Ala	synonymous_variant	Exon 27 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4293G>A	p.Ala1431Ala	synonymous_variant	Exon 27 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4293G>A	p.Ala1431Ala	synonymous_variant	Exon 27 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4293G>A	p.Ala1431Ala	synonymous_variant	Exon 27 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4152G>A	p.Ala1384Ala	synonymous_variant	Exon 26 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4293G>A	p.Ala1431Ala	synonymous_variant	Exon 27 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4302G>A	p.Ala1434Ala	synonymous_variant	Exon 27 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4293G>A	p.Ala1431Ala	synonymous_variant	Exon 27 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4296G>A	p.Ala1432Ala	synonymous_variant	Exon 27 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4293G>A	p.Ala1431Ala	synonymous_variant	Exon 27 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4293G>A	p.Ala1431Ala	synonymous_variant	Exon 27 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4293G>A	p.Ala1431Ala	synonymous_variant	Exon 27 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152124 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000451 AC: 11 AN: 243658 Hom.: 0 AF XY: 0.0000606 AC XY: 8 AN XY: 131948

Gnomad AFR exome AF: 0.000268

Gnomad AMR exome AF: 0.0000589

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1458702 Hom.: 0 Cov.: 31 AF XY: 0.0000207 AC XY: 15 AN XY: 725220

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000451

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000586

Gnomad4 FIN exome AF: 0.0000938

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152242 Hom.: 0 Cov.: 29 AF XY: 0.0000672 AC XY: 5 AN XY: 74444

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000529

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Dec 22, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.2
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: rs555959123; hg19: chr19-13370476;