chr2-53767983-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001008708.4(CHAC2):ā€‹c.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

Scores

10
5
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.55
Variant links:
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]

Genome browser will be placed here

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
CHAC2NM_001008708.4 linkuse as main transcriptc.97T>C p.Trp33Arg missense_variant 1/3 ENST00000295304.5 NP_001008708.1
ASB3NM_016115.5 linkuse as main transcriptc.-13-2398A>G intron_variant ENST00000263634.8 NP_057199.1
GPR75-ASB3NM_001164165.2 linkuse as main transcriptc.102-2398A>G intron_variant NP_001157637.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CHAC2ENST00000295304.5 linkuse as main transcriptc.97T>C p.Trp33Arg missense_variant 1/31 NM_001008708.4 ENSP00000295304 P1
ASB3ENST00000263634.8 linkuse as main transcriptc.-13-2398A>G intron_variant 1 NM_016115.5 ENSP00000263634 P1Q9Y575-1

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152064
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.000324
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000143
AC:
36
AN:
250926
Hom.:
0
AF XY:
0.000147
AC XY:
20
AN XY:
135692
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000578
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:
0.000282
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000400
AC:
584
AN:
1461724
Hom.:
0
Cov.:
31
AF XY:
0.000391
AC XY:
284
AN XY:
727186
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000224
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:
0.000472
Gnomad4 OTH exome
AF:
0.000911
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152064
Hom.:
0
Cov.:
33
AF XY:
0.0000807
AC XY:
6
AN XY:
74306
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.000324
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000330
Hom.:
0
Bravo
AF:
0.000230
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000115
AC:
14
EpiCase
AF:
0.000491
EpiControl
AF:
0.000297

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 submitterclinical testingAmbry GeneticsMay 20, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Uncertain
0.099
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Benign
0.23
T
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.84
T
M_CAP
Benign
0.068
D
MetaRNN
Pathogenic
0.88
D
MetaSVM
Uncertain
-0.18
T
MutationAssessor
Pathogenic
3.8
H
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-9.1
D
REVEL
Uncertain
0.56
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.99
D
Vest4
0.94
MutPred
0.80
Gain of disorder (P = 0.0012);
MVP
0.67
MPC
0.0046
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.97
gMVP
0.85

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: rs201804249; hg19: chr2-53995120; API