19-53982539-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031895.6(CACNG8):​c.968C>T​(p.Ala323Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000707 in 1,230,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

CACNG8
NM_031895.6 missense

Scores

1
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.236
Variant links:
Genes affected
CACNG8 (HGNC:13628): (calcium voltage-gated channel auxiliary subunit gamma 8) The protein encoded by this gene is a type I transmembrane AMPA receptor regulatory protein (TARP). TARPs regulate both trafficking and channel gating of the AMPA receptors. This gene is part of a functionally diverse eight-member protein subfamily of the PMP-22/EMP/MP20 family and is located in a cluster with two family members, a type II TARP and a calcium channel gamma subunit. The mRNA for this gene is believed to initiate translation from a non-AUG (CUG) start codon. [provided by RefSeq, Dec 2010]
MIR935 (HGNC:33678): (microRNA 935) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13220578).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNG8NM_031895.6 linkc.968C>T p.Ala323Val missense_variant Exon 4 of 4 ENST00000270458.4 NP_114101.4 Q8WXS5
MIR935NR_030632.1 linkn.*142C>T downstream_gene_variant
MIR935unassigned_transcript_3404 n.*155C>T downstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNG8ENST00000270458.4 linkc.968C>T p.Ala323Val missense_variant Exon 4 of 4 1 NM_031895.6 ENSP00000270458.3 Q8WXS5A0A1X7SBR8
MIR935ENST00000401179.1 linkn.*142C>T downstream_gene_variant 6

Frequencies

GnomAD3 genomes
AF:
0.0000544
AC:
8
AN:
147188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000123
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000421
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000151
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000729
AC:
79
AN:
1082966
Hom.:
0
Cov.:
33
AF XY:
0.0000974
AC XY:
50
AN XY:
513096
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:
0.00193
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000347
Gnomad4 OTH exome
AF:
0.0000462
GnomAD4 genome
AF:
0.0000544
AC:
8
AN:
147188
Hom.:
0
Cov.:
32
AF XY:
0.0000558
AC XY:
4
AN XY:
71632
show subpopulations
Gnomad4 AFR
AF:
0.000123
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000421
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000151
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000214
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 14, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.968C>T (p.A323V) alteration is located in exon 4 (coding exon 4) of the CACNG8 gene. This alteration results from a C to T substitution at nucleotide position 968, causing the alanine (A) at amino acid position 323 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.074
.;T
Eigen
Benign
-0.44
Eigen_PC
Benign
-0.38
FATHMM_MKL
Benign
0.21
N
LIST_S2
Benign
0.53
T;T
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.13
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
.;N
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
-0.25
N;.
REVEL
Benign
0.035
Sift
Benign
0.11
T;.
Sift4G
Uncertain
0.028
D;.
Polyphen
0.38
.;B
Vest4
0.11
MutPred
0.32
Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);
MVP
0.27
ClinPred
0.24
T
GERP RS
0.83
Varity_R
0.066
gMVP
0.19

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: rs1033326564; hg19: chr19-54485793; API