rs121909315

Positions:

• chr19-13303576-G-T
• chr19-13303576-G-A
• chr19-13303576-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1 PM1 PM2 PP2 PP3_Moderate PP5

The NM_001127222.2(CACNA1A):​c.2142C>A​(p.Asp714Glu) variant causes a missense change involving the alteration of a non-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). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 29)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.786

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 12 ACMG points.

• PS1: Transcript NM_001127222.2 (CACNA1A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a repeat II (size 244) in uniprot entity CAC1A_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) 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, 0.853
• PP5: Variant 19-13303576-G-T is Pathogenic according to our data. Variant chr19-13303576-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 8497.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.2142C>A	p.Asp714Glu	missense_variant	17/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2142C>A	p.Asp714Glu	missense_variant	17/47	1	NM_001127222.2	ENSP00000353362

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Migraine, familial hemiplegic, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 20, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.5	.;.;.;.;M;.;.;M;.;.;.;.;M;.;.
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.86
MutPred		0.43		Gain of disorder (P = 0.1529);.;Gain of disorder (P = 0.1529);Gain of disorder (P = 0.1529);Gain of disorder (P = 0.1529);.;Gain of disorder (P = 0.1529);Gain of disorder (P = 0.1529);Gain of disorder (P = 0.1529);Gain of disorder (P = 0.1529);Gain of disorder (P = 0.1529);.;Gain of disorder (P = 0.1529);.;Gain of disorder (P = 0.1529);
MVP		0.97
MPC		2.2
ClinPred		0.99	D
GERP RS		1.4
Varity_R		0.73
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs121908218; hg19: chr19-13414390;