rs755221106

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_018896.5(CACNA1G):c.5144G>A(p.Arg1715His) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

CACNA1G
NM_018896.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 10.0

Variant links:

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]

CACNA1G links:

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ACMG classification

Classification made for transcript

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, 0.976

PP5

Variant 17-50617560-G-A is Pathogenic according to our data. Variant chr17-50617560-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 221981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1G	NM_018896.5 linkuse as main transcript	c.5144G>A	p.Arg1715His	missense_variant	29/38	ENST00000359106.10	NP_061496.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1G	ENST00000359106.10 linkuse as main transcript	c.5144G>A	p.Arg1715His	missense_variant	29/38	1	NM_018896.5	ENSP00000352011	A2	O43497-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spinocerebellar ataxia type 42

Pathogenic:4

Pathogenic, criteria provided, single submitter	research	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	Jan 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 02, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 14, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 05, 2021	The CACNA1G c. 5144G>A variant is classified as a PATHOGENIC variant (PS4, PS3, PP1_Strong, PP3, PP5) The variant is a single nucleotide change from a guanine to an adenine at position 5144 which is predicted to change the Arginine at position 1715 in the protein to Histidine. The variant is in exon 29 and is located in protein domains: ion transport domain, and Polycystin cation channel, of the CACNA1G gene. This variant is a recurrent pathogenic variant in the CACNA1G gene, and it has been previously reported in many individuals with Cerebellar ataxias in heterozygoys state (PMID: 26456284, 26715324, 28490766, 29629410) (PS4). This variant is in dbSNP (rs755221106) but is absent from population databases. In vitro functonal studies have demonstrated that this variant had resulted in a significant shift of the steady-state activation curve towards more positive membrane potential values, whereas the inactivation curve had a higher slope factor, supporting the damaging effect on the gene or gene product (PMID: 26456284, 26715324) (PS3). Multiple pedigrees of Cerebellar ataxia-affected families with this variant has been previously reported showing segregation of this variant with the disorder (PMID: PMID: 26456284, 26715324, 28490766, 29629410) (PP1_Strong). The variant has been reported in the ClinVar (Variation ID: 221981) and HGMD (Accession: CM1511857) as Pathogenic (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2022	Published functional studies demonstrate a damaging effect on membrane potential dependency (Coutelier et al., 2015; Morino et al., 2015); 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: 29915382, 34426522, 30200108, 29474447, 35054808, 29421541, 31892274, 30842224, 32878331, 32638069, 34248568, 31999455, 34220096, 33746731, 31229688, 33243296, 31836334, 28490766, 26715324, 33624863, 31692161, 26456284, 29629410, 33163565, 31217264) -

Spinocerebellar ataxia type 42;C4748120:Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

CACNA1G-related disorder

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

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

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.98

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

0.99

MutationAssessor

Pathogenic

4.5

.;.;.;.;.;.;.;.;.;.;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

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-4.9

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

0.94

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.

Vest4

0.83

MutPred

0.85

.;.;.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0487);.;.;Loss of MoRF binding (P = 0.0487);.;Loss of MoRF binding (P = 0.0487);.;.;.;.;Loss of MoRF binding (P = 0.0487);.;.;Loss of MoRF binding (P = 0.0487);.;

MVP

0.99

MPC

2.6

ClinPred

1.0

GERP RS

5.0

Varity_R

0.96

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over