17-50561518-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_018896.5(CACNA1G):c.59T>C(p.Met20Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,385,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: CACNA1G NM_018896.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.120

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CACNA1G
• BP4: Computational evidence support a benign effect (MetaRNN=0.09073618).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1G	NM_018896.5	c.59T>C	p.Met20Thr	missense_variant	1/38	ENST00000359106.10
CACNA1G-AS1	NR_038439.1	n.181+410A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1G	ENST00000359106.10	c.59T>C	p.Met20Thr	missense_variant	1/38	1	NM_018896.5	A2
CACNA1G-AS1	ENST00000505793.1	n.181+410A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1385040 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 683540

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 25, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	11
Dann	Benign	0.76
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.70	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
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.091	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	-0.27	T
MutationAssessor	Benign	0.0	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
MutationTaster	Benign	1.0	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
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.54	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	0.32
Sift	Benign	0.35	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	0.80	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		0.0	.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;B;.
Vest4		0.081
MutPred		0.28		Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);Gain of phosphorylation at M20 (P = 0.0093);
MVP		0.52
MPC		1.4
ClinPred		0.034	T
GERP RS		0.50
Varity_R		0.065
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-48638879;