rs886041505

Positions:

• chr17-50592063-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_018896.5(CACNA1G):​c.2881G>A​(p.Ala961Thr) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1G NM_018896.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 10.0

Genes affected

CACNA1G (HGNC:1394): (calcium voltage-gated channel subunit alpha1 G) Voltage-sensitive 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, gene expression, cell motility, cell division, and cell death. This gene encodes a T-type, low-voltage activated calcium channel. The T-type channels generate currents that are both transient, owing to fast inactivation, and tiny, owing to small conductance. T-type channels are thought to be involved in pacemaker activity, low-threshold calcium spikes, neuronal oscillations and resonance, and rebound burst firing. Many alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1G. . Gene score misZ 4.6386 (greater than the threshold 3.09). Trascript score misZ 5.0317 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, spinocerebellar ataxia type 42, spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 17-50592063-G-A is Pathogenic according to our data. Variant chr17-50592063-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 280269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1G	NM_018896.5	c.2881G>A	p.Ala961Thr	missense_variant	13/38	ENST00000359106.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1G	ENST00000359106.10	c.2881G>A	p.Ala961Thr	missense_variant	13/38	1	NM_018896.5	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jul 10, 2023	The heterozygous variant c.2881G>A (p.Ala961Thr) has been identified in a proband with global developmental delay, sparse hair, decreased tone, speech defects, inability to handle objects, stranger anxiety, axial hypotonia, limb hypotonia, dystonia and increased levels of glutaric acid on GCMS. This variant has not been reported in gnomAD (aggregated) database (PM2_moderate). Computational tools predict a deleterious effect of the mis-sense variant (PP3_moderate). This variant has been reported previously (PP5_supporting). PMID: 29878067. Segregation in the parents confirms that this is a de-novo variant in the proband. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 14, 2018	- -

Neurodevelopmental abnormality Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Jun 04, 2020

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2024

The c.2881G>A (p.A961T) alteration is located in coding exon 13 of the CACNA1G gene. This alteration results from a G to A substitution at nucleotide position 2881, causing the alanine (A) at amino acid position 961 to be replaced by a threonine (T). The CACNA1G c.2881G>A alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individual(s) with features consistent with CACNA1G-related spinocerebellar ataxia (Chemin, 2018; Martinez-Rubio, 2023). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 20, 2022

Published functional studies of the A961T variant demonstrate a gain of function effect by impairing the inactivation of the channel (Chemin et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29878067, 31217264, 33098379, 32736238, 31836334, 31785789, 30842224) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	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;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H;H;H;.;H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D;.
Vest4		0.92
MutPred		0.73		Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);Gain of glycosylation at A961 (P = 0.0577);
MVP		0.97
MPC		2.5
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.83
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: rs886041505; hg19: chr17-48669424;