chr2-53774193-G-T

Variant names:

• chr2-53774193-G-T
• rs768260163
• NM_001008708.4:c.223G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001008708.4(CHAC2):​c.223G>T​(p.Val75Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,148 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V75I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHAC2 NM_001008708.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.06
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.223G>T	p.Val75Leu	missense	Exon 3 of 3	NP_001008708.1	Q8WUX2
	ASB3	NM_016115.5	MANE Select	c.-13-8608C>A		intron	N/A	NP_057199.1	Q9Y575-1
	CHAC2	NM_001346127.1		c.55G>T	p.Val19Leu	missense	Exon 3 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.223G>T	p.Val75Leu	missense	Exon 3 of 3	ENSP00000295304.4	Q8WUX2
	ASB3	ENST00000263634.8	TSL:1 MANE Select	c.-13-8608C>A		intron	N/A	ENSP00000263634.2	Q9Y575-1
	CHAC2	ENST00000893858.1		c.187G>T	p.Val63Leu	missense	Exon 2 of 2	ENSP00000563917.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461148 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726862

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111786

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		8.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.28
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.051	T
Polyphen		0.43	B
Vest4		0.67
MutPred		0.69		Loss of ubiquitination at K76 (P = 0.1343)
MVP		0.34
MPC		0.0054
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.82
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

dbSNP: rs768260163; hg19: chr2-54001330;