chr19-13230191-C-A

Variant names:

• chr19-13230191-C-A
• rs1555736565
• NM_001127222.2:c.5419G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001127222.2(CACNA1A):​c.5419G>T​(p.Ala1807Ser) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1807T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.82
• Publications: 0 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: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-13230191-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 500851.We mark this variant Pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 19-13230191-C-A is Pathogenic according to our data. Variant chr19-13230191-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5419G>T	p.Ala1807Ser	missense_variant	Exon 36 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5419G>T	p.Ala1807Ser	missense_variant	Exon 36 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5437G>T	p.Ala1813Ser	missense_variant	Exon 37 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5425G>T	p.Ala1809Ser	missense_variant	Exon 36 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5422G>T	p.Ala1808Ser	missense_variant	Exon 36 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5422G>T	p.Ala1808Ser	missense_variant	Exon 36 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5422G>T	p.Ala1808Ser	missense_variant	Exon 36 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5281G>T	p.Ala1761Ser	missense_variant	Exon 35 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5422G>T	p.Ala1808Ser	missense_variant	Exon 36 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5437G>T	p.Ala1813Ser	missense_variant	Exon 37 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5428G>T	p.Ala1810Ser	missense_variant	Exon 37 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5425G>T	p.Ala1809Ser	missense_variant	Exon 36 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5422G>T	p.Ala1808Ser	missense_variant	Exon 36 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5422G>T	p.Ala1808Ser	missense_variant	Exon 36 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5422G>T	p.Ala1808Ser	missense_variant	Exon 36 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.5422G>T		non_coding_transcript_exon_variant	Exon 36 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*600G>T		non_coding_transcript_exon_variant	Exon 37 of 47			ENSP00000519091.1
CACNA1A	ENST00000713789.1	n.*600G>T		3_prime_UTR_variant	Exon 37 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1808 of the CACNA1A protein (p.Ala1808Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CACNA1A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 523409). 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%. This variant disrupts the p.Ala1808 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 35217970; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Strabismus;C0557874:Global developmental delay;C1858120:Generalized hypotonia Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;.;T;.;.;.;.;.;D;.;.;T;.;.;.;T;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0040	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.79
MutPred		0.77		.;.;Loss of catalytic residue at A1808 (P = 0.1587);Loss of catalytic residue at A1808 (P = 0.1587);Loss of catalytic residue at A1808 (P = 0.1587);.;.;Loss of catalytic residue at A1808 (P = 0.1587);.;.;.;Loss of catalytic residue at A1808 (P = 0.1587);Loss of catalytic residue at A1808 (P = 0.1587);.;Loss of catalytic residue at A1808 (P = 0.1587);.;.;.;
MVP		0.96
MPC		2.0
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.57
gMVP		0.95
Mutation Taster		=20/80	disease causing (ClinVar)

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: rs1555736565; hg19: chr19-13341005;