rs121908214

Variant names:

• chr19-13230185-T-C
• NM_001127222.2:c.5425A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-13230185-T-C
• chr19-13230185-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_001127222.2(CACNA1A):​c.5425A>G​(p.Ile1809Val) 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. I1809L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.93

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 11 ACMG points.

• PM1: In a repeat IV (size 263) 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-13230185-T-G is described in Lovd as [Likely_pathogenic].
• 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, 0.881
• PP5: Variant 19-13230185-T-C is Pathogenic according to our data. Variant chr19-13230185-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2942672.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5425A>G	p.Ile1809Val	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.5425A>G	p.Ile1809Val	missense_variant	Exon 36 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5443A>G	p.Ile1815Val	missense_variant	Exon 37 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5431A>G	p.Ile1811Val	missense_variant	Exon 36 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5428A>G	p.Ile1810Val	missense_variant	Exon 36 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5428A>G	p.Ile1810Val	missense_variant	Exon 36 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5428A>G	p.Ile1810Val	missense_variant	Exon 36 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5287A>G	p.Ile1763Val	missense_variant	Exon 35 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5428A>G	p.Ile1810Val	missense_variant	Exon 36 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5443A>G	p.Ile1815Val	missense_variant	Exon 37 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5434A>G	p.Ile1812Val	missense_variant	Exon 37 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5431A>G	p.Ile1811Val	missense_variant	Exon 36 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5428A>G	p.Ile1810Val	missense_variant	Exon 36 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5428A>G	p.Ile1810Val	missense_variant	Exon 36 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5428A>G	p.Ile1810Val	missense_variant	Exon 36 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.52A>G		non_coding_transcript_exon_variant	Exon 2 of 10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Feb 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. This variant disrupts the p.Ile1810 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8898206, 9488686, 10024348, 12235360). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1810 of the CACNA1A protein (p.Ile1810Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.99	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.80
MutPred		0.65		.;.;Gain of catalytic residue at I1810 (P = 0.0672);Gain of catalytic residue at I1810 (P = 0.0672);Gain of catalytic residue at I1810 (P = 0.0672);.;.;Gain of catalytic residue at I1810 (P = 0.0672);.;.;.;Gain of catalytic residue at I1810 (P = 0.0672);Gain of catalytic residue at I1810 (P = 0.0672);.;Gain of catalytic residue at I1810 (P = 0.0672);.;.;.;
MVP		0.93
MPC		1.1
ClinPred		0.91	D
GERP RS		4.3
Varity_R		0.42
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-13340999;