chr19-13261501-C-G

Position:

• chr19-13261501-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The ENST00000360228.11(CACNA1A):​c.4199G>C​(p.Gly1400Ala) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1400E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A ENST00000360228.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

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 Likely_pathogenic. Variant got 7 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, 4 uncertain in ENST00000360228.11
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4199G>C	p.Gly1400Ala	missense_variant	26/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4199G>C	p.Gly1400Ala	missense_variant	26/47	1	NM_001127222.2	ENSP00000353362

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 24, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 947721). 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 glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1401 of the CACNA1A protein (p.Gly1401Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;.;.;.;M;.;.;.;.;.;.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.9	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0060	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.82
MutPred		0.58		.;.;Gain of catalytic residue at G1401 (P = 0.0378);Gain of catalytic residue at G1401 (P = 0.0378);Gain of catalytic residue at G1401 (P = 0.0378);.;Gain of catalytic residue at G1401 (P = 0.0378);.;.;Gain of catalytic residue at G1401 (P = 0.0378);Gain of catalytic residue at G1401 (P = 0.0378);.;Gain of catalytic residue at G1401 (P = 0.0378);.;Gain of catalytic residue at G1401 (P = 0.0378);
MVP		0.95
MPC		2.5
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.78
gMVP		0.99

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: rs1555745111; hg19: chr19-13372315;