19-13334394-C-T

Variant names:

• chr19-13334394-C-T
• rs2248069
• NM_001127222.2:c.1182G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001127222.2(CACNA1A):​c.1182G>A​(p.Glu394Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 1,585,238 control chromosomes in the GnomAD database, including 368,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (32054 hom., cov: 31)
  • Exomes 𝑓: 0.68 (336063 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.500
• Publications: 23 publications found

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 Gene-Disease associations (from GenCC):

• episodic ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• developmental and epileptic encephalopathy, 42

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• migraine, familial hemiplegic, 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• benign paroxysmal torticollis of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 19-13334394-C-T is Benign according to our data. Variant chr19-13334394-C-T is described in ClinVar as Benign. ClinVar VariationId is 93559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.1182G>A	p.Glu394Glu	synonymous_variant	Exon 8 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1182G>A	p.Glu394Glu	synonymous_variant	Exon 8 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1182G>A	p.Glu394Glu	synonymous_variant	Exon 8 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1182G>A	p.Glu394Glu	synonymous_variant	Exon 8 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1182G>A	p.Glu394Glu	synonymous_variant	Exon 8 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1182G>A	p.Glu394Glu	synonymous_variant	Exon 8 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1182G>A	p.Glu394Glu	synonymous_variant	Exon 8 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1041G>A	p.Glu347Glu	synonymous_variant	Exon 7 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1182G>A	p.Glu394Glu	synonymous_variant	Exon 8 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1182G>A	p.Glu394Glu	synonymous_variant	Exon 8 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1182G>A	p.Glu394Glu	synonymous_variant	Exon 8 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1182G>A	p.Glu394Glu	synonymous_variant	Exon 8 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1182G>A	p.Glu394Glu	synonymous_variant	Exon 8 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1182G>A	p.Glu394Glu	synonymous_variant	Exon 8 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1182G>A	p.Glu394Glu	synonymous_variant	Exon 8 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.1182G>A		non_coding_transcript_exon_variant	Exon 8 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.1182G>A		non_coding_transcript_exon_variant	Exon 8 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.645 AC: 97846 AN: 151808 Hom.: 32030 Cov.: 31

Gnomad AFR AF: 0.527

Gnomad AMI AF: 0.722

Gnomad AMR AF: 0.739

Gnomad ASJ AF: 0.644

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.716

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.647

GnomAD2 exomes AF: 0.688 AC: 171545 AN: 249230 AF XY: 0.689

Gnomad AFR exome AF: 0.521

Gnomad AMR exome AF: 0.800

Gnomad ASJ exome AF: 0.651

Gnomad EAS exome AF: 0.639

Gnomad FIN exome AF: 0.685

Gnomad NFE exome AF: 0.680

Gnomad OTH exome AF: 0.679

GnomAD4 exome AF: 0.683 AC: 978972 AN: 1433312 Hom.: 336063 Cov.: 28 AF XY: 0.685 AC XY: 489389 AN XY: 714748

African (AFR) AF: 0.510 AC: 16790 AN: 32916

American (AMR) AF: 0.794 AC: 35497 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 16967 AN: 25974

East Asian (EAS) AF: 0.666 AC: 26327 AN: 39550

South Asian (SAS) AF: 0.719 AC: 61630 AN: 85696

European-Finnish (FIN) AF: 0.687 AC: 36665 AN: 53386

Middle Eastern (MID) AF: 0.613 AC: 3495 AN: 5706

European-Non Finnish (NFE) AF: 0.683 AC: 741441 AN: 1085986

Other (OTH) AF: 0.676 AC: 40160 AN: 59414

GnomAD4 genome AF: 0.644 AC: 97914 AN: 151926 Hom.: 32054 Cov.: 31 AF XY: 0.647 AC XY: 48045 AN XY: 74236

African (AFR) AF: 0.527 AC: 21799 AN: 41392

American (AMR) AF: 0.739 AC: 11270 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 2235 AN: 3470

East Asian (EAS) AF: 0.635 AC: 3266 AN: 5146

South Asian (SAS) AF: 0.716 AC: 3442 AN: 4804

European-Finnish (FIN) AF: 0.681 AC: 7204 AN: 10574

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.684 AC: 46484 AN: 67966

Other (OTH) AF: 0.649 AC: 1372 AN: 2114

Alfa AF: 0.667 Hom.: 61160

Bravo AF: 0.641

Asia WGS AF: 0.717 AC: 2494 AN: 3478

EpiCase AF: 0.679

EpiControl AF: 0.671

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jan 07, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 96% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 89. Only high quality variants are reported. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 09, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 6 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Episodic ataxia type 2 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Migraine, familial hemiplegic, 1 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Developmental and epileptic encephalopathy, 42 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	8.0
DANN	Benign	0.49
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2248069; hg19: chr19-13445208; COSMIC: COSV64191907;