NM_018896.5:c.2881G>A

Variant names:

• chr17-50592063-G-A
• rs886041505
• NM_018896.5:c.2881G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
CACNA1G	NM_018896.5	c.2881G>A	p.Ala961Thr	missense_variant	Exon 13 of 38	ENST00000359106.10	NP_061496.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1G	ENST00000359106.10	c.2881G>A	p.Ala961Thr	missense_variant	Exon 13 of 38	1	NM_018896.5	ENSP00000352011.5
CACNA1G	ENST00000507510.6	c.2881G>A	p.Ala961Thr	missense_variant	Exon 13 of 37	1		ENSP00000423112.2

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

Aug 14, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 10, 2023

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Neurodevelopmental abnormality Pathogenic:1

Jun 04, 2020

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jun 04, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 20, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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;