chr19-13231847-C-T

Position:

• chr19-13231847-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001127222.2(CACNA1A):​c.5263G>A​(p.Glu1755Lys) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.78

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 10 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
• 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). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. GenCC has associacion of the 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, 0.954
• PP5: Variant 19-13231847-C-T is Pathogenic according to our data. Variant chr19-13231847-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8500.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5263G>A	p.Glu1755Lys	missense_variant	35/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5263G>A	p.Glu1755Lys	missense_variant	35/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5281G>A	p.Glu1761Lys	missense_variant	36/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5269G>A	p.Glu1757Lys	missense_variant	35/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5266G>A	p.Glu1756Lys	missense_variant	35/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5266G>A	p.Glu1756Lys	missense_variant	35/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5266G>A	p.Glu1756Lys	missense_variant	35/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5125G>A	p.Glu1709Lys	missense_variant	34/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5266G>A	p.Glu1756Lys	missense_variant	35/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5281G>A	p.Glu1761Lys	missense_variant	36/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5272G>A	p.Glu1758Lys	missense_variant	36/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5269G>A	p.Glu1757Lys	missense_variant	35/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5266G>A	p.Glu1756Lys	missense_variant	35/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5266G>A	p.Glu1756Lys	missense_variant	35/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5266G>A	p.Glu1756Lys	missense_variant	35/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Episodic ataxia type 2 Pathogenic:1 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 04, 2007	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;.;T;.;.;.;.;.;D;.;.;T;.;.;.;T;.;.;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.95	D;D;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	3.3	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.032	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.88
MutPred		0.81		.;.;Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);.;.;Gain of MoRF binding (P = 0.0056);.;.;.;Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);.;Gain of MoRF binding (P = 0.0056);.;.;.;.;.;
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.82
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: rs121908226; hg19: chr19-13342661;