2-53774317-C-G

Position:

• chr2-53774317-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001008708.4(CHAC2):​c.347C>G​(p.Pro116Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,880 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHAC2 NM_001008708.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

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:):

ACMG classification

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, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHAC2	NM_001008708.4	c.347C>G	p.Pro116Arg	missense_variant	3/3	ENST00000295304.5	NP_001008708.1
ASB3	NM_016115.5	c.-13-8732G>C		intron_variant		ENST00000263634.8	NP_057199.1
GPR75-ASB3	NM_001164165.2	c.102-8732G>C		intron_variant			NP_001157637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHAC2	ENST00000295304.5	c.347C>G	p.Pro116Arg	missense_variant	3/3	1	NM_001008708.4	ENSP00000295304	P1
ASB3	ENST00000263634.8	c.-13-8732G>C		intron_variant		1	NM_016115.5	ENSP00000263634	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460880 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726720

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2023

The c.347C>G (p.P116R) alteration is located in exon 3 (coding exon 3) of the CHAC2 gene. This alteration results from a C to G substitution at nucleotide position 347, causing the proline (P) at amino acid position 116 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	Benign	0.15
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.64		Gain of solvent accessibility (P = 0.0411);
MVP		0.55
MPC		0.0059
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.75
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-54001454;