19-13262771-C-T

Variant names:

• chr19-13262771-C-T
• rs1555745467
• NM_001127222.2:c.4052G>A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001127222.2(CACNA1A):​c.4052G>A​(p.Arg1351Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.81

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S4 of repeat III (size 18) in uniprot entity CAC1A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CACNA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. Gene score misZ: 5.7845 (above the threshold of 3.09). Trascript score misZ: 3.9354 (above the threshold of 3.09). GenCC associations: The gene is linked to benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 19-13262771-C-T is Pathogenic according to our data. Variant chr19-13262771-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 971813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13262771-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4052G>A	p.Arg1351Gln	missense_variant	Exon 25 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4052G>A	p.Arg1351Gln	missense_variant	Exon 25 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4064G>A	p.Arg1355Gln	missense_variant	Exon 25 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4058G>A	p.Arg1353Gln	missense_variant	Exon 25 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4055G>A	p.Arg1352Gln	missense_variant	Exon 25 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4055G>A	p.Arg1352Gln	missense_variant	Exon 25 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4055G>A	p.Arg1352Gln	missense_variant	Exon 25 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3914G>A	p.Arg1305Gln	missense_variant	Exon 24 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4055G>A	p.Arg1352Gln	missense_variant	Exon 25 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4064G>A	p.Arg1355Gln	missense_variant	Exon 25 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4055G>A	p.Arg1352Gln	missense_variant	Exon 25 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4058G>A	p.Arg1353Gln	missense_variant	Exon 25 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4055G>A	p.Arg1352Gln	missense_variant	Exon 25 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4055G>A	p.Arg1352Gln	missense_variant	Exon 25 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4055G>A	p.Arg1352Gln	missense_variant	Exon 25 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461274 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726902

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 42 Pathogenic:2

Apr 15, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS2,PS4,PM2_SUP,PM5_SUP,PP2,PP3 -

May 26, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine (exon 25). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0601 - Variant affects at least one well-established (essential) functional domain or motif. The altered amino acid has been described as functionally-important in the voltage-sensing region of CACNA1A protein (PMID:18597946). (P) 0704 - Comparable variant has low previous evidence for pathogenicity. An alternative change to a leucine, p.(R1352L), has been reported as likely pathogenic in ClinVar. (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in patients with CACNA1A-related disorders, or seizures and global developmental delay, including de novo in 2 of the patients (VCGS, Deciphering Developmental Disorders (DDD) Study, PMID:31115040). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Episodic ataxia type 2 Pathogenic:1

Aug 17, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.98 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.67 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000971813 /PMID: 29997391). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29997391). A different missense change at the same codon (p.Arg1351Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000450236). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Spinocerebellar ataxia type 6 Pathogenic:1

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Feb 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1352 of the CACNA1A protein (p.Arg1352Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CACNA1A-related conditions (PMID: 28007337, 29997391, 33425808). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 971813). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Apr 14, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4055G>A (p.R1352Q) alteration is located in exon 25 (coding exon 25) of the CACNA1A gene. This alteration results from a G to A substitution at nucleotide position 4055, causing the arginine (R) at amino acid position 1352 to be replaced by a glutamine (Q)._x000D_ _x000D_ Based on the available evidence, the CACNA1A c.4055G>A (p.R1352Q) alteration is classified as pathogenic for CACNA1A-related neurologic disorders; however, it is unlikely to be causative of CACNA1A-related spinocerebellar ataxia and its clinical significance for episodic ataxia type 2 is unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with CACNA1A-related neurologic disorders (Travaglini, 2017; Valence, 2018; Gauquelin, 2020; Humbertclaude, 2020; Zhang, 2020; Stubberud, 2021; Valentino, 2021). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Jul 28, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34356170, 34758253, 33163565, 29997391, 34806130, 33790770, 33425808, 28007337) -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4479236:Developmental and epileptic encephalopathy, 52 Pathogenic:1

Mar 20, 2022

Wendy Chung Laboratory, Columbia University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CACNA1A-related disorder Pathogenic:1

Jul 26, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PS4, PM2, PP2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	5.1	.;.;.;.;H;.;.;.;.;.;.;.;H;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.93
MutPred		0.94		.;.;Loss of methylation at R1352 (P = 0.0878);Loss of methylation at R1352 (P = 0.0878);Loss of methylation at R1352 (P = 0.0878);.;Loss of methylation at R1352 (P = 0.0878);.;.;Loss of methylation at R1352 (P = 0.0878);Loss of methylation at R1352 (P = 0.0878);.;Loss of methylation at R1352 (P = 0.0878);.;Loss of methylation at R1352 (P = 0.0878);
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.82
gMVP		1.0

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: rs1555745467; hg19: chr19-13373585; COSMIC: COSV104420638; COSMIC: COSV104420638;