19-13365413-C-T

Position:

• chr19-13365413-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_001127222.2(CACNA1A):​c.688G>A​(p.Gly230Ser) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• 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]

CACNA1A (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a repeat I (size 278) in uniprot entity CAC1A_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_001127222.2
• 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, 0.85
• PP5: Variant 19-13365413-C-T is Pathogenic according to our data. Variant chr19-13365413-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 476276.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.688G>A	p.Gly230Ser	missense_variant	5/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.688G>A	p.Gly230Ser	missense_variant	5/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.688G>A	p.Gly230Ser	missense_variant	5/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.688G>A	p.Gly230Ser	missense_variant	5/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.688G>A	p.Gly230Ser	missense_variant	5/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.688G>A	p.Gly230Ser	missense_variant	5/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.688G>A	p.Gly230Ser	missense_variant	5/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.547G>A	p.Gly183Ser	missense_variant	4/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.688G>A	p.Gly230Ser	missense_variant	5/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.688G>A	p.Gly230Ser	missense_variant	5/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.688G>A	p.Gly230Ser	missense_variant	5/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.688G>A	p.Gly230Ser	missense_variant	5/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.688G>A	p.Gly230Ser	missense_variant	5/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.688G>A	p.Gly230Ser	missense_variant	5/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.688G>A	p.Gly230Ser	missense_variant	5/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 12, 2022

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 230 of the CACNA1A protein (p.Gly230Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hemiplegic migraine (Invitae). ClinVar contains an entry for this variant (Variation ID: 476276). 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. This variant disrupts the p.Gly230 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31468518). 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. -

Developmental and epileptic encephalopathy, 42 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Aug 08, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;D;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.74	.;N;.;.;N;.;.;N;.;.;.;.;N;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.85
Sift	Benign	0.10	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.025	D;D;.;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen		0.99	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.68
MutPred		0.66		Loss of catalytic residue at G230 (P = 0.0648);Loss of catalytic residue at G230 (P = 0.0648);Loss of catalytic residue at G230 (P = 0.0648);Loss of catalytic residue at G230 (P = 0.0648);Loss of catalytic residue at G230 (P = 0.0648);.;Loss of catalytic residue at G230 (P = 0.0648);Loss of catalytic residue at G230 (P = 0.0648);Loss of catalytic residue at G230 (P = 0.0648);Loss of catalytic residue at G230 (P = 0.0648);Loss of catalytic residue at G230 (P = 0.0648);Loss of catalytic residue at G230 (P = 0.0648);Loss of catalytic residue at G230 (P = 0.0648);Loss of catalytic residue at G230 (P = 0.0648);Loss of catalytic residue at G230 (P = 0.0648);
MVP		0.94
MPC		2.3
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.69
gMVP		0.96

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: rs1555774859; hg19: chr19-13476227;