chr2-53767892-G-C

Position:

chr2-53767892-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001008708.4(CHAC2):c.6G>C(p.Trp2Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000646 in 1,610,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

CHAC2
NM_001008708.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.64

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]

CHAC2 links:

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]

ASB3 links:

GPR75-ASB3 (HGNC:40043): (GPR75-ASB3 readthrough) This locus represents naturally occurring read-through transcription between the neighboring GPR75 (G protein-coupled receptor 75) and ASB3 (ankyrin repeat and SOCS box containing 3) on chromosome 2. The transcript includes exons from both GPR75 and ASB3 and translation initiates in the 5' non-coding exon of GPR75. The resulting protein has a novel N-terminus but is otherwise identical to that encoded by ASB3.[provided by RefSeq, Feb 2011]

GPR75-ASB3 links:

ASB3 (HGNC:):

ASB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHAC2	NM_001008708.4 linkuse as main transcript	c.6G>C	p.Trp2Cys	missense_variant	1/3	ENST00000295304.5	NP_001008708.1	Q8WUX2
ASB3	NM_016115.5 linkuse as main transcript	c.-13-2307C>G		intron_variant		ENST00000263634.8	NP_057199.1	Q9Y575-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHAC2	ENST00000295304.5 linkuse as main transcript	c.6G>C	p.Trp2Cys	missense_variant	1/3	1	NM_001008708.4	ENSP00000295304.4		Q8WUX2
ASB3	ENST00000263634.8 linkuse as main transcript	c.-13-2307C>G		intron_variant		1	NM_016115.5	ENSP00000263634.2		Q9Y575-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152198

Hom.:

Cov.:

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000578

AC:

AN:

242108

Hom.:

AF XY:

0.0000688

AC XY:

AN XY:

130896

show subpopulations

Gnomad AFR exome

AF:

0.0000652

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:

0.000110

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.0000631

AC:

AN:

1458574

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

725212

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:

0.0000801

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74358

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:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

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 11, 2022

The c.6G>C (p.W2C) alteration is located in exon 1 (coding exon 1) of the CHAC2 gene. This alteration results from a G to C substitution at nucleotide position 6, causing the tryptophan (W) at amino acid position 2 to be replaced by a cysteine (C). 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

0.97

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.19

MutationAssessor

Pathogenic

3.5

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-11

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.94

MutPred

0.84

Loss of MoRF binding (P = 0.0579);

MVP

0.69

MPC

0.0052

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.97

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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