chr17-50561536-C-G

Position:

chr17-50561536-C-G

Variant summary

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

The NM_018896.5(CACNA1G):c.77C>G(p.Ser26Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000215 in 1,537,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S26S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CACNA1G
NM_018896.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.74

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 GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1G	NM_018896.5 linkuse as main transcript	c.77C>G	p.Ser26Trp	missense_variant	1/38	ENST00000359106.10
CACNA1G-AS1	NR_038439.1 linkuse as main transcript	n.181+392G>C		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.77C>G	p.Ser26Trp	missense_variant	1/38	1	NM_018896.5	A2	O43497-1
CACNA1G-AS1	ENST00000505793.1 linkuse as main transcript	n.181+392G>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000791

AC:

AN:

151770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000149

AC:

AN:

134248

Hom.:

AF XY:

0.0000136

AC XY:

AN XY:

73566

show subpopulations

Gnomad AFR exome

AF:

0.000308

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000152

AC:

AN:

1386094

Hom.:

Cov.:

AF XY:

0.0000117

AC XY:

AN XY:

684036

show subpopulations

Gnomad4 AFR exome

AF:

0.000539

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:

0.00

Gnomad4 OTH exome

AF:

0.0000692

GnomAD4 genome

AF:

0.0000791

AC:

AN:

151770

Hom.:

Cov.:

AF XY:

0.0000675

AC XY:

AN XY:

74106

show subpopulations

Gnomad4 AFR

AF:

0.000266

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000299

Hom.:

Bravo

AF:

0.0000718

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 01, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 33526774) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.0017

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

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

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.97

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

0.86

MetaRNN

Uncertain

0.63

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

MetaSVM

Uncertain

0.63

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

1.0

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

0.91

PROVEAN

Uncertain

-2.7

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

0.58

Sift

Pathogenic

0.0

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

0.0070

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

Polyphen

1.0, 1.0, 0.83

.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;P;.

Vest4

0.48

MutPred

0.32

Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);Loss of phosphorylation at S26 (P = 0.0172);

MVP

0.89

MPC

2.8

ClinPred

0.89

GERP RS

2.8

Varity_R

0.50

gMVP

0.67

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