rs4902346

Variant names:

• chr14-64940442-A-G
• rs4902346
• NM_002083.4:c.223-604T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002083.4(GPX2):​c.223-604T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 152,010 control chromosomes in the GnomAD database, including 6,107 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (6107 hom., cov: 32)
• Consequence: GPX2 NM_002083.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.502
• Publications: 21 publications found

Genes affected

GPX2 (HGNC:4554): (glutathione peroxidase 2) The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of organic hydroperoxides and hydrogen peroxide (H2O2) by glutathione, and thereby protect cells against oxidative damage. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. This isozyme is predominantly expressed in the gastrointestinal tract (also in liver in human), is localized in the cytoplasm, and whose preferred substrate is hydrogen peroxide. Overexpression of this gene is associated with increased differentiation and proliferation in colorectal cancer. This isozyme is also a selenoprotein, containing the rare amino acid selenocysteine (Sec) at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2016]

CHURC1-FNTB (HGNC:42960): (CHURC1-FNTB readthrough) This locus represents naturally occurring read-through transcription between the neighboring CHURC1 (churchill domain containing 1) and FNTB (farnesyltransferase, CAAX box, beta) on chromosome 14. The read-through transcript produces a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Feb 2011]

CHURC1 (HGNC:20099): (churchill domain containing 1) Predicted to enable zinc ion binding activity. Predicted to be involved in positive regulation of transcription, DNA-templated. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002083.4. 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
	GPX2	NM_002083.4	MANE Select	c.223-604T>C		intron	N/A	NP_002074.2
	CHURC1-FNTB	NM_001202559.1		c.327+14362A>G		intron	N/A	NP_001189488.1	B4DL54
	CHURC1-FNTB	NM_001202558.2		c.6+16316A>G		intron	N/A	NP_001189487.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX2	ENST00000389614.6	TSL:1 MANE Select	c.223-604T>C		intron	N/A	ENSP00000374265.5	P18283
	CHURC1-FNTB	ENST00000549987.1	TSL:2	c.246+14362A>G		intron	N/A	ENSP00000447121.2	B4DL54
	GPX2	ENST00000553522.1	TSL:1	n.223-244T>C		intron	N/A	ENSP00000450991.1	G3V323

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40195 AN: 151892 Hom.: 6082 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.237

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.265 AC: 40283 AN: 152010 Hom.: 6107 Cov.: 32 AF XY: 0.267 AC XY: 19813 AN XY: 74330

African (AFR) AF: 0.406 AC: 16818 AN: 41422

American (AMR) AF: 0.205 AC: 3129 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1051 AN: 3466

East Asian (EAS) AF: 0.130 AC: 675 AN: 5176

South Asian (SAS) AF: 0.292 AC: 1410 AN: 4822

European-Finnish (FIN) AF: 0.232 AC: 2447 AN: 10566

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13836 AN: 67964

Other (OTH) AF: 0.241 AC: 509 AN: 2112

Alfa AF: 0.233 Hom.: 1517

Bravo AF: 0.270

Asia WGS AF: 0.259 AC: 899 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.4
DANN	Benign	0.65
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4902346; hg19: chr14-65407160;