rs1057519429

Positions:

• chr19-13235666-C-G
• chr19-13235666-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_001127222.2(CACNA1A):​c.5015G>C​(p.Arg1672Pro) 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: 31)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 7.86

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 Pathogenic. Variant got 11 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). 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, 0.946
• PP5: Variant 19-13235666-C-G is Pathogenic according to our data. Variant chr19-13235666-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375366.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-13235666-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5015G>C	p.Arg1672Pro	missense_variant	32/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5015G>C	p.Arg1672Pro	missense_variant	32/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5033G>C	p.Arg1678Pro	missense_variant	33/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5021G>C	p.Arg1674Pro	missense_variant	32/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5018G>C	p.Arg1673Pro	missense_variant	32/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5018G>C	p.Arg1673Pro	missense_variant	32/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5018G>C	p.Arg1673Pro	missense_variant	32/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4877G>C	p.Arg1626Pro	missense_variant	31/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5018G>C	p.Arg1673Pro	missense_variant	32/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5033G>C	p.Arg1678Pro	missense_variant	33/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5024G>C	p.Arg1675Pro	missense_variant	33/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5021G>C	p.Arg1674Pro	missense_variant	32/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5018G>C	p.Arg1673Pro	missense_variant	32/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5018G>C	p.Arg1673Pro	missense_variant	32/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5018G>C	p.Arg1673Pro	missense_variant	32/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4479236:Developmental and epileptic encephalopathy, 52 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Wendy Chung Laboratory, Columbia University Medical Center

Mar 20, 2022

- -

Cerebellar ataxia;C0740279:Cerebellar atrophy;C3714756:Intellectual disability Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Undiagnosed Diseases Network, NIH

Dec 19, 2015

Likely pathogenicity based on finding it once in our study de novo in an 8-year-old female with delayed motor milestones, delayed speech, progressive cerebellar atrophy, hypotonia, and problems with coordination. Our patient has been reported in PMCID:PMC5557584 (patient 1). -

CACNA1A-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 10, 2024

The CACNA1A c.5015G>C variant is predicted to result in the amino acid substitution p.Arg1672Pro. This variant has been confirmed to be de novo in two unrelated individuals with CACNA1A-related disorders (Eldomery et al. 2017. PubMed ID: 28327206; Luo et al. 2017. PubMed ID: 28742085). In vivo modeling of this variant showed alternation in channel activation consistent with a gain-of-function effect (Luo et al. 2017. PubMed ID: 28742085; Tyagi et al. 2019. PubMed ID: 31015257). This variant has not been reported in a large population database, indicating this variant is rare and it is classified as likely pathogenic/pathogenic in ClinVar. Given the evidence, we interpret this variant as likely pathogenic. -

Cerebellar ataxia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

-

This variant was identified, de novo, in an individual with non-fluctuating ataxia. -

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	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;.;T;.;.;.;.;.;D;.;.;T;.;.;.;T;.;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.70	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	3.0	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.75
MutPred		0.77		.;.;Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);.;.;Loss of MoRF binding (P = 0.0054);.;.;.;Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);.;Loss of MoRF binding (P = 0.0054);.;.;.;.;.;
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057519429; hg19: chr19-13346480;