NM_001127222.2:c.4072C>T

Variant names:

• chr19-13262751-G-A
• rs1555745461
• NM_001127222.2:c.4072C>T

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.4072C>T​(p.Arg1358Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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:5
• Conservation: PhyloP100: 4.83

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 repeat III (size 283) in uniprot entity CAC1A_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) 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, 0.941
• PP5: Variant 19-13262751-G-A is Pathogenic according to our data. Variant chr19-13262751-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 448996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13262751-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4072C>T	p.Arg1358Trp	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.4072C>T	p.Arg1358Trp	missense_variant	Exon 25 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4084C>T	p.Arg1362Trp	missense_variant	Exon 25 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4078C>T	p.Arg1360Trp	missense_variant	Exon 25 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4075C>T	p.Arg1359Trp	missense_variant	Exon 25 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4075C>T	p.Arg1359Trp	missense_variant	Exon 25 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4075C>T	p.Arg1359Trp	missense_variant	Exon 25 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3934C>T	p.Arg1312Trp	missense_variant	Exon 24 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4075C>T	p.Arg1359Trp	missense_variant	Exon 25 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4084C>T	p.Arg1362Trp	missense_variant	Exon 25 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4075C>T	p.Arg1359Trp	missense_variant	Exon 25 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4078C>T	p.Arg1360Trp	missense_variant	Exon 25 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4075C>T	p.Arg1359Trp	missense_variant	Exon 25 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4075C>T	p.Arg1359Trp	missense_variant	Exon 25 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4075C>T	p.Arg1359Trp	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: 1459360 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726020

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jan 22, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 19, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed 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: 24091540, 26863999, 31618753) -

Apr 22, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene. Computational tools predict that this variant is damaging. -

CACNA1A-associated disorders Pathogenic:1

May 24, 2019

Clinical Genomics Laboratory, Stanford Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Arg1359Trp variant in the CACNA1A gene has been previously reported de novo in two unrelated individuals, one individual with early onset epilepsy, ataxia, dysmetria, oculomotor apraxia, tremor, developmental delay, intellectual disability, speech delay, hypotonia, and pyramidal sign (Ohba et al., 2013), and one individual with an undescribed neurological condition (Nolan and Carlson, 2015). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The CACNA1A gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. Computational tools predict that the p.Arg1359Trp variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg1359Trp variant as likely pathogenic for CACNA1A-assocatied disorders in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PS2; PM2; PP2; PP3] -

Delayed gross motor development Pathogenic:1

-

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	.;.;.;.;H;.;.;.;.;.;.;.;H;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.9	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.94
MutPred		0.72		.;.;Loss of phosphorylation at T1356 (P = 0.0773);Loss of phosphorylation at T1356 (P = 0.0773);Loss of phosphorylation at T1356 (P = 0.0773);.;Loss of phosphorylation at T1356 (P = 0.0773);.;.;Loss of phosphorylation at T1356 (P = 0.0773);Loss of phosphorylation at T1356 (P = 0.0773);.;Loss of phosphorylation at T1356 (P = 0.0773);.;Loss of phosphorylation at T1356 (P = 0.0773);
MVP		0.96
MPC		2.5
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.88
gMVP		0.98

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: rs1555745461; hg19: chr19-13373565;