chr17-50561605-A-T

Position:

chr17-50561605-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_018896.5(CACNA1G):c.146A>T(p.Glu49Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000662 in 1,586,416 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

CACNA1G
NM_018896.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.981

Variant links:

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 links:

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

CACNA1G-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 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.

BS2

High AC in GnomAdExome4 at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1G	NM_018896.5 linkuse as main transcript	c.146A>T	p.Glu49Val	missense_variant	1/38	ENST00000359106.10
CACNA1G-AS1	NR_038439.1 linkuse as main transcript	n.181+323T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1G	ENST00000359106.10 linkuse as main transcript	c.146A>T	p.Glu49Val	missense_variant	1/38	1	NM_018896.5	A2	O43497-1
CACNA1G-AS1	ENST00000505793.1 linkuse as main transcript	n.181+323T>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000103

AC:

AN:

194902

Hom.:

AF XY:

0.00000926

AC XY:

AN XY:

107938

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000718

AC:

103

AN:

1434642

Hom.:

Cov.:

AF XY:

0.0000492

AC XY:

AN XY:

711280

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000918

Gnomad4 OTH exome

AF:

0.0000337

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151774

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74146

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2022

CACNA1G: PP2, PP3 -

CACNA1G-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2023

The CACNA1G c.146A>T variant is predicted to result in the amino acid substitution p.Glu49Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0024% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-48638966-A-T). 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

Uncertain

0.36

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.061

.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.89

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

0.65

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

0.90

MutationAssessor

Benign

1.8

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

0.69

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

0.89

PROVEAN

Uncertain

-3.1

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

REVEL

Uncertain

0.57

Sift

Uncertain

0.0090

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

Uncertain

0.054

T;D;T;T;D;D;T;T;T;T;T;D;D;D;T;D;T;T;D;T;T;T;D;T;D;T

Polyphen

0.94, 0.92, 0.50

.;.;.;.;.;P;.;.;.;.;.;.;.;.;.;.;P;.;.;.;.;.;.;.;P;.

Vest4

0.30

MutPred

0.39

Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);

MVP

0.92

MPC

2.4

ClinPred

0.83

GERP RS

2.8

Varity_R

0.23

gMVP

0.62

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over