2-53774424-A-G

Position:

• chr2-53774424-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001008708.4(CHAC2):​c.454A>G​(p.Ile152Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000461 in 1,612,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: CHAC2 NM_001008708.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.440

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014508009).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHAC2	NM_001008708.4	c.454A>G	p.Ile152Val	missense_variant	3/3	ENST00000295304.5	NP_001008708.1
ASB3	NM_016115.5	c.-13-8839T>C		intron_variant		ENST00000263634.8	NP_057199.1
GPR75-ASB3	NM_001164165.2	c.102-8839T>C		intron_variant			NP_001157637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHAC2	ENST00000295304.5	c.454A>G	p.Ile152Val	missense_variant	3/3	1	NM_001008708.4	ENSP00000295304	P1
ASB3	ENST00000263634.8	c.-13-8839T>C		intron_variant		1	NM_016115.5	ENSP00000263634	P1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.000485

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000321 AC: 80 AN: 249048 Hom.: 0 AF XY: 0.000290 AC XY: 39 AN XY: 134460

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000763

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000339

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000398

Gnomad OTH exome AF: 0.000823

GnomAD4 exome AF: 0.000477 AC: 697 AN: 1459724 Hom.: 0 Cov.: 31 AF XY: 0.000446 AC XY: 324 AN XY: 725918

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000813

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000469

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000568

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000268 AC XY: 20 AN XY: 74494

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000464 Hom.: 0

Bravo AF: 0.000325

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000288 AC: 35

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000764

EpiControl AF: 0.000593

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

Sep 16, 2021

The c.454A>G (p.I152V) alteration is located in exon 3 (coding exon 3) of the CHAC2 gene. This alteration results from a A to G substitution at nucleotide position 454, causing the isoleucine (I) at amino acid position 152 to be replaced by a valine (V). 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	0.071
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.87
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.074
Sift	Benign	0.22	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.076
MPC		0.0027
ClinPred		0.0054	T
GERP RS		0.42
Varity_R		0.052
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs145424430; hg19: chr2-54001561;