rs886041505

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000330170: Published functional studies of the A961T variant demonstrate a gain of function effect by impairing the inactivation of the channel (Chemin et al., 2018)".

• 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
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• spinocerebellar ataxia type 42

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina
• intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000330170: Published functional studies of the A961T variant demonstrate a gain of function effect by impairing the inactivation of the channel (Chemin et al., 2018)
• 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 VariationId is 280269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018896.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1G	NM_018896.5	MANE Select	c.2881G>A	p.Ala961Thr	missense	Exon 13 of 38	NP_061496.2
	CACNA1G	NM_198377.3		c.2881G>A	p.Ala961Thr	missense	Exon 13 of 37	NP_938191.2	O43497-20
	CACNA1G	NM_198396.3		c.2881G>A	p.Ala961Thr	missense	Exon 13 of 36	NP_938406.1	O43497-33

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1G	ENST00000359106.10	TSL:1 MANE Select	c.2881G>A	p.Ala961Thr	missense	Exon 13 of 38	ENSP00000352011.5	O43497-1
	CACNA1G	ENST00000507336.5	TSL:1	c.2881G>A	p.Ala961Thr	missense	Exon 13 of 37	ENSP00000420918.1	O43497-20
	CACNA1G	ENST00000507510.6	TSL:1	c.2881G>A	p.Ala961Thr	missense	Exon 13 of 37	ENSP00000423112.2	O43497-12

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 248914 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neurodevelopmental abnormality (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		10
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.73		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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886041505; hg19: chr17-48669424;