rs150378053

Positions:

• chr19-13255218-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001127222.2(CACNA1A):​c.4632C>T​(p.Thr1544Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,610,046 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0018 (5 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.24

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-13255218-G-A is Benign according to our data. Variant chr19-13255218-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 166766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13255218-G-A is described in Lovd as [Benign]. Variant chr19-13255218-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00179 (273/152264) while in subpopulation AMR AF= 0.00412 (63/15288). AF 95% confidence interval is 0.00331. There are 1 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 273 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4632C>T	p.Thr1544Thr	synonymous_variant	29/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4632C>T	p.Thr1544Thr	synonymous_variant	29/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4644C>T	p.Thr1548Thr	synonymous_variant	29/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4638C>T	p.Thr1546Thr	synonymous_variant	29/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4635C>T	p.Thr1545Thr	synonymous_variant	29/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4635C>T	p.Thr1545Thr	synonymous_variant	29/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4635C>T	p.Thr1545Thr	synonymous_variant	29/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4494C>T	p.Thr1498Thr	synonymous_variant	28/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4635C>T	p.Thr1545Thr	synonymous_variant	29/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4644C>T	p.Thr1548Thr	synonymous_variant	29/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4635C>T	p.Thr1545Thr	synonymous_variant	29/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4638C>T	p.Thr1546Thr	synonymous_variant	29/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4635C>T	p.Thr1545Thr	synonymous_variant	29/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4635C>T	p.Thr1545Thr	synonymous_variant	29/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4635C>T	p.Thr1545Thr	synonymous_variant	29/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152146 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00185 AC: 460 AN: 248210 Hom.: 1 AF XY: 0.00186 AC XY: 251 AN XY: 134710

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00401

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00185 AC: 2696 AN: 1457782 Hom.: 5 Cov.: 31 AF XY: 0.00185 AC XY: 1337 AN XY: 724330

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.00417

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.00210

Gnomad4 OTH exome AF: 0.00135

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152264 Hom.: 1 Cov.: 30 AF XY: 0.00175 AC XY: 130 AN XY: 74444

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00256

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00214 Hom.: 0

Bravo AF: 0.00203

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CACNA1A: BP4, BP7 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 16, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 28, 2015	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2016

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. -

CACNA1A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 03, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.2
DANN	Benign	0.80

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: rs150378053; hg19: chr19-13366032;