chr1-193096669-G-A

Position:

• chr1-193096669-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_197962.3(GLRX2):​c.451C>T​(p.His151Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000612 in 1,596,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (0 hom.)
• Consequence: GLRX2 NM_197962.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.72

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09922877).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRX2	NM_197962.3	c.451C>T	p.His151Tyr	missense_variant	4/4	ENST00000367439.8	NP_932066.1
GLRX2	NM_016066.4	c.454C>T	p.His152Tyr	missense_variant	4/4		NP_057150.2
GLRX2	NM_001243399.2	c.331C>T	p.His111Tyr	missense_variant	4/4		NP_001230328.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRX2	ENST00000367439.8	c.451C>T	p.His151Tyr	missense_variant	4/4	1	NM_197962.3	ENSP00000356409.3
GLRX2	ENST00000367440.3	c.454C>T	p.His152Tyr	missense_variant	4/4	1		ENSP00000356410.3
GLRX2	ENST00000472197.1	n.772C>T		splice_region_variant, non_coding_transcript_exon_variant	4/4	5
GLRX2	ENST00000608166.2	n.451C>T		non_coding_transcript_exon_variant	4/5	6		ENSP00000494652.1

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000460 AC: 115 AN: 250042 Hom.: 0 AF XY: 0.000451 AC XY: 61 AN XY: 135202

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000987

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.000849

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.000623 AC: 900 AN: 1443964 Hom.: 0 Cov.: 26 AF XY: 0.000606 AC XY: 436 AN XY: 719396

Gnomad4 AFR exome AF: 0.0000906

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.000743

Gnomad4 OTH exome AF: 0.000736

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74366

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.000927

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000805 Hom.: 0

Bravo AF: 0.000431

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.00126

EpiControl AF: 0.000356

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

Oct 06, 2022

The c.454C>T (p.H152Y) alteration is located in exon 4 (coding exon 4) of the GLRX2 gene. This alteration results from a C to T substitution at nucleotide position 454, causing the histidine (H) at amino acid position 152 to be replaced by a tyrosine (Y). 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	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.099	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.098
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.70	P;D
Vest4		0.28
MVP		0.52
MPC		0.60
ClinPred		0.16	T
GERP RS		5.5
Varity_R		0.62
gMVP		0.51

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

LitVar

Other links and lift over

dbSNP: rs141929600; hg19: chr1-193065799; COSMIC: COSV105301934; COSMIC: COSV105301934;