rs781240948

Positions:

• chr17-50568971-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_018896.5(CACNA1G):​c.344G>A​(p.Arg115Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000772 in 1,425,096 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000077 (1 hom.)
• Consequence: CACNA1G NM_018896.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38

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 Likely_benign. Variant got -5 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22062734).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1G	NM_018896.5	c.344G>A	p.Arg115Gln	missense_variant	2/38	ENST00000359106.10	NP_061496.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1G	ENST00000359106.10	c.344G>A	p.Arg115Gln	missense_variant	2/38	1	NM_018896.5	ENSP00000352011.5
CACNA1G	ENST00000507510.6	c.344G>A	p.Arg115Gln	missense_variant	2/37	1		ENSP00000423112.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000167 AC: 4 AN: 239546 Hom.: 0 AF XY: 0.0000230 AC XY: 3 AN XY: 130398

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000772 AC: 11 AN: 1425096 Hom.: 1 Cov.: 32 AF XY: 0.0000127 AC XY: 9 AN XY: 709864

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000390

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000706

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000277

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000248 AC: 3

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

Aug 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.
Eigen	Benign	0.014
Eigen_PC	Benign	0.089
FATHMM_MKL	Benign	0.68	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;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.22	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	Uncertain	0.78	D
MutationAssessor	Benign	0.62	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
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	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	0.45
Sift	Benign	0.26	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
Sift4G	Benign	0.64	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		0.88, 1.0, 0.062	.;.;.;.;.;P;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;B;.
Vest4		0.17
MutPred		0.50		Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);
MVP		0.91
MPC		1.4
ClinPred		0.48	T
GERP RS		3.6
Varity_R		0.11
gMVP		0.44

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: rs781240948; hg19: chr17-48646332;