2-53767905-G-A

Variant names:

• chr2-53767905-G-A
• rs373020166
• NM_001008708.4:c.19G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001008708.4(CHAC2):​c.19G>A​(p.Gly7Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CHAC2 NM_001008708.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.64
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008708.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAC2	NM_001008708.4	MANE Select	c.19G>A	p.Gly7Arg	missense	Exon 1 of 3	NP_001008708.1	Q8WUX2
	ASB3	NM_016115.5	MANE Select	c.-13-2320C>T		intron	N/A	NP_057199.1	Q9Y575-1
	CHAC2	NM_001346127.1		c.-155G>A		5_prime_UTR	Exon 1 of 3	NP_001333056.1	Q8WUX2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAC2	ENST00000295304.5	TSL:1 MANE Select	c.19G>A	p.Gly7Arg	missense	Exon 1 of 3	ENSP00000295304.4	Q8WUX2
	ASB3	ENST00000263634.8	TSL:1 MANE Select	c.-13-2320C>T		intron	N/A	ENSP00000263634.2	Q9Y575-1
	CHAC2	ENST00000893858.1		c.19G>A	p.Gly7Arg	missense	Exon 1 of 2	ENSP00000563917.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246516 AF XY: 0.00000750

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460388 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726360

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000225 AC: 1 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39646

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111452

Other (OTH) AF: 0.00 AC: 0 AN: 60288

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		9.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.070	T
Polyphen		1.0	D
Vest4		0.92
MutPred		0.90		Gain of MoRF binding (P = 6e-04)
MVP		0.91
MPC		0.0069
ClinPred		1.0	D
GERP RS		4.5
PromoterAI		-0.057	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.99
gMVP		0.92
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs373020166; hg19: chr2-53995042;