rs943715197

Positions:

• chr19-13253050-C-A
• chr19-13253050-C-T

Variant summary

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

The NM_001127222.2(CACNA1A):​c.4807G>T​(p.Val1603Phe) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1603I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.15

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 repeat IV (size 263) in uniprot entity CAC1A_HUMAN there are 54 pathogenic changes around while only 11 benign (83%) 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, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.4807G>T	p.Val1603Phe	missense_variant	30/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4807G>T	p.Val1603Phe	missense_variant	30/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Episodic ataxia type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	.;.;T;.;.;.;.;.;.;.;T;.;.;.;T;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.0	.;.;.;.;L;.;.;.;.;.;.;.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.4	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.022	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.070	T;T;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.81
MutPred		0.71		.;.;Loss of stability (P = 0.0655);Loss of stability (P = 0.0655);Loss of stability (P = 0.0655);.;.;Loss of stability (P = 0.0655);.;.;Loss of stability (P = 0.0655);Loss of stability (P = 0.0655);.;Loss of stability (P = 0.0655);.;Loss of stability (P = 0.0655);.;
MVP		0.97
MPC		2.7
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.57
gMVP		0.98

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: rs943715197; hg19: chr19-13363864;