rs886041505

chr17-50592063-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1G NM_018896.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CACNA1G
• 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 280269.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

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

- -

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) -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2018

- -

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
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;