rs121908233

Positions:

• chr19-13257474-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001127222.2(CACNA1A):​c.4466T>C​(p.Phe1489Ser) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.25

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 9 ACMG points.

• PM1: In a repeat III (size 283) 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). 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, 0.934
• PP5: Variant 19-13257474-A-G is Pathogenic according to our data. Variant chr19-13257474-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8498.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4466T>C	p.Phe1489Ser	missense_variant	28/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4466T>C	p.Phe1489Ser	missense_variant	28/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4478T>C	p.Phe1493Ser	missense_variant	28/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4472T>C	p.Phe1491Ser	missense_variant	28/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4469T>C	p.Phe1490Ser	missense_variant	28/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4469T>C	p.Phe1490Ser	missense_variant	28/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4469T>C	p.Phe1490Ser	missense_variant	28/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4328T>C	p.Phe1443Ser	missense_variant	27/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4469T>C	p.Phe1490Ser	missense_variant	28/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4478T>C	p.Phe1493Ser	missense_variant	28/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4469T>C	p.Phe1490Ser	missense_variant	28/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4472T>C	p.Phe1491Ser	missense_variant	28/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4469T>C	p.Phe1490Ser	missense_variant	28/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4469T>C	p.Phe1490Ser	missense_variant	28/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4469T>C	p.Phe1490Ser	missense_variant	28/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Episodic ataxia type 2 Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2001	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely pathogenic, criteria provided, single submitter	research	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	Jul 12, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	.;.;.;.;H;.;.;.;.;.;.;.;H;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.9	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.96
MutPred		0.69		.;.;Loss of stability (P = 0.0042);Loss of stability (P = 0.0042);Loss of stability (P = 0.0042);.;Loss of stability (P = 0.0042);.;.;Loss of stability (P = 0.0042);Loss of stability (P = 0.0042);.;Loss of stability (P = 0.0042);.;Loss of stability (P = 0.0042);.;
MVP		1.0
MPC		3.0
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.91
gMVP		1.0

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: rs121908233; hg19: chr19-13368288;