rs1555565684

Positions:

• chr17-50616335-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_018896.5(CACNA1G):​c.4972T>C​(p.Ser1658Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1G NM_018896.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1G	NM_018896.5	c.4972T>C	p.Ser1658Pro	missense_variant	28/38	ENST00000359106.10	NP_061496.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1G	ENST00000359106.10	c.4972T>C	p.Ser1658Pro	missense_variant	28/38	1	NM_018896.5	ENSP00000352011.5
CACNA1G	ENST00000507510.6	c.4972T>C	p.Ser1658Pro	missense_variant	28/37	1		ENSP00000423112.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 42 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	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
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.93	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	Uncertain	2.1	.;.;.;.;.;.;.;.;.;.;M;.;.;M;.;M;.;.;.;.;M;.;.;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.2	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	0.83
Sift	Uncertain	0.0020	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	Uncertain	0.0020	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, 1.0	.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Vest4		0.83
MutPred		0.77		.;.;.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0896);.;.;Loss of MoRF binding (P = 0.0896);.;Loss of MoRF binding (P = 0.0896);.;.;.;.;Loss of MoRF binding (P = 0.0896);.;.;Loss of MoRF binding (P = 0.0896);.;
MVP		0.94
MPC		2.5
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.96
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555565684; hg19: chr17-48693696;