chr2-53767983-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001008708.4(CHAC2):āc.97T>Cā(p.Trp33Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000376 in 1,613,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.00015 ( 0 hom., cov: 33)
Exomes š: 0.00040 ( 0 hom. )
Consequence
CHAC2
NM_001008708.4 missense
NM_001008708.4 missense
Scores
10
5
4
Clinical Significance
Conservation
PhyloP100: 7.55
Genes affected
CHAC2 (HGNC:32363): (ChaC glutathione specific gamma-glutamylcyclotransferase 2) The protein encoded by this gene is a gamma-glutamyl cyclotransferase that catalyzes the conversion of glutathione to 5-oxoproline and cysteinylglycine. It is thought that this gene is upregulated in response to endoplasmic reticulum stress and that the glutathione depletion enhances apoptosis. [provided by RefSeq, Sep 2016]
ASB3 (HGNC:16013): (ankyrin repeat and SOCS box containing 3) The protein encoded by this gene is a member of the ankyrin repeat and SOCS box-containing (ASB) family of proteins. They contain ankyrin repeat sequence and SOCS box domain. The SOCS box serves to couple suppressor of cytokine signalling (SOCS) proteins and their binding partners with the elongin B and C complex, possibly targeting them for degradation. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.885
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHAC2 | NM_001008708.4 | c.97T>C | p.Trp33Arg | missense_variant | 1/3 | ENST00000295304.5 | NP_001008708.1 | |
ASB3 | NM_016115.5 | c.-13-2398A>G | intron_variant | ENST00000263634.8 | NP_057199.1 | |||
GPR75-ASB3 | NM_001164165.2 | c.102-2398A>G | intron_variant | NP_001157637.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHAC2 | ENST00000295304.5 | c.97T>C | p.Trp33Arg | missense_variant | 1/3 | 1 | NM_001008708.4 | ENSP00000295304 | P1 | |
ASB3 | ENST00000263634.8 | c.-13-2398A>G | intron_variant | 1 | NM_016115.5 | ENSP00000263634 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152064Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000143 AC: 36AN: 250926Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135692
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GnomAD4 exome AF: 0.000400 AC: 584AN: 1461724Hom.: 0 Cov.: 31 AF XY: 0.000391 AC XY: 284AN XY: 727186
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GnomAD4 genome AF: 0.000151 AC: 23AN: 152064Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74306
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 20, 2024 | The c.97T>C (p.W33R) alteration is located in exon 1 (coding exon 1) of the CHAC2 gene. This alteration results from a T to C substitution at nucleotide position 97, causing the tryptophan (W) at amino acid position 33 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0012);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at