1-193097645-T-C

Position:

• chr1-193097645-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_197962.3(GLRX2):​c.299A>G​(p.Asp100Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRX2 NM_197962.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96

Genes affected

GLRX2 (HGNC:16065): (glutaredoxin 2) The protein encoded by this gene is a member of the glutaredoxin family of proteins, which maintain cellular thiol homeostasis. These proteins are thiol-disulfide oxidoreductases that use a glutathione-binding site and one or two active cysteines in their active site. This gene undergoes alternative splicing to produce multiple isoforms, one of which is ubiquitously expressed and localizes to mitochondria, where it functions in mitochondrial redox homeostasis and is important for the protection against and recovery from oxidative stress. Other isoforms, which have more restrictive expression patterns, show cytosolic and nuclear localization, and are thought to function in cellular differentiation and transformation, possibly with a role in tumor progression. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRX2	NM_197962.3	c.299A>G	p.Asp100Gly	missense_variant	3/4	ENST00000367439.8	NP_932066.1
GLRX2	NM_016066.4	c.302A>G	p.Asp101Gly	missense_variant	3/4		NP_057150.2
GLRX2	NM_001243399.2	c.179A>G	p.Asp60Gly	missense_variant	3/4		NP_001230328.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRX2	ENST00000367439.8	c.299A>G	p.Asp100Gly	missense_variant	3/4	1	NM_197962.3	ENSP00000356409.3
GLRX2	ENST00000367440.3	c.302A>G	p.Asp101Gly	missense_variant	3/4	1		ENSP00000356410.3
GLRX2	ENST00000472197.1	n.620A>G		non_coding_transcript_exon_variant	3/4	5
GLRX2	ENST00000608166.2	n.299A>G		non_coding_transcript_exon_variant	3/5	6		ENSP00000494652.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

May 26, 2023

The c.302A>G (p.D101G) alteration is located in exon 3 (coding exon 3) of the GLRX2 gene. This alteration results from a A to G substitution at nucleotide position 302, causing the aspartic acid (D) at amino acid position 101 to be replaced by a glycine (G). 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	0.81
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.7	H;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.64
MutPred		0.66		Loss of ubiquitination at K95 (P = 0.1045);.;
MVP		0.64
MPC		0.48
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.88
gMVP		0.86

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: chr1-193066775;