17-50561562-G-A

Position:

• chr17-50561562-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_018896.5(CACNA1G):​c.103G>A​(p.Gly35Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1G NM_018896.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.30

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-AS1 (HGNC:27377): (CACNA1G antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1G	NM_018896.5	c.103G>A	p.Gly35Arg	missense_variant	1/38	ENST00000359106.10
CACNA1G-AS1	NR_038439.1	n.181+366C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1G	ENST00000359106.10	c.103G>A	p.Gly35Arg	missense_variant	1/38	1	NM_018896.5	A2
CACNA1G-AS1	ENST00000505793.1	n.181+366C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

CACNA1G-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 19, 2024

The CACNA1G c.103G>A variant is predicted to result in the amino acid substitution p.Gly35Arg. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.88	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	0.82	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Benign	1.4	L;L;L;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L
MutationTaster	Benign	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;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.015	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	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 1.0, 0.90	.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;P;.
Vest4		0.42
MutPred		0.26		Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);
MVP		0.92
MPC		2.6
ClinPred		0.81	D
GERP RS		1.8
Varity_R		0.15
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1275474414; hg19: chr17-48638923;