chr17-50578391-A-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_018896.5(CACNA1G):​c.2128A>T​(p.Ser710Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,613,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

CACNA1G
NM_018896.5 missense

Scores

7
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -0.106
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.2003806).
BP6
Variant 17-50578391-A-T is Benign according to our data. Variant chr17-50578391-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 208689.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000869 (127/1461026) while in subpopulation NFE AF= 0.000112 (125/1111822). AF 95% confidence interval is 0.0000961. There are 0 homozygotes in gnomad4_exome. There are 50 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1GNM_018896.5 linkc.2128A>T p.Ser710Cys missense_variant 9/38 ENST00000359106.10 NP_061496.2 O43497-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1GENST00000359106.10 linkc.2128A>T p.Ser710Cys missense_variant 9/381 NM_018896.5 ENSP00000352011.5 O43497-1
CACNA1GENST00000507510.6 linkc.2128A>T p.Ser710Cys missense_variant 9/371 ENSP00000423112.2 O43497-12

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000281
AC:
7
AN:
248670
Hom.:
0
AF XY:
0.0000370
AC XY:
5
AN XY:
134978
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:
0.0000533
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000869
AC:
127
AN:
1461026
Hom.:
0
Cov.:
33
AF XY:
0.0000688
AC XY:
50
AN XY:
726804
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:
0.000112
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.0000483
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:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000838
Hom.:
0
Bravo
AF:
0.0000340
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000331
AC:
4
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 10, 2025- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 03, 2022In 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 -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 09, 2021The c.2128A>T (p.S710C) alteration is located in exon 9 (coding exon 9) of the CACNA1G gene. This alteration results from a A to T substitution at nucleotide position 2128, causing the serine (S) at amino acid position 710 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 20, 2024Variant summary: CACNA1G c.2128A>T (p.Ser710Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-05 in 1606190 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database (v4.1 dataset). The occurrence in several carriers suggests that this variant is likely not causal for a penetrant dominant condition. To our knowledge, no occurrence of c.2128A>T in individuals affected with Spinocerebellar Ataxia Type 42 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 208689). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.046
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.063
.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.
Eigen
Benign
-0.45
Eigen_PC
Benign
-0.50
FATHMM_MKL
Benign
0.18
N
LIST_S2
Uncertain
0.91
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
Benign
0.061
D
MetaRNN
Benign
0.20
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
0.31
D
MutationAssessor
Benign
1.5
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
PrimateAI
Benign
0.34
T
PROVEAN
Uncertain
-2.5
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
0.31
Sift
Uncertain
0.020
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
0.051
T;T;T;T;D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.0, 0.77, 0.67
.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;P;.;.;.;.;.;.;.;P;.
Vest4
0.43
MVP
0.81
MPC
0.15
ClinPred
0.56
D
GERP RS
-1.9
Varity_R
0.10
gMVP
0.45

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.

Other links and lift over

dbSNP: rs543673731; hg19: chr17-48655752; API