14-64942486-A-T

Variant names:

• chr14-64942486-A-T
• rs1800669
• NM_002083.4:c.222+19T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002083.4(GPX2):​c.222+19T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,604,084 control chromosomes in the GnomAD database, including 603 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 0.019 (37 hom., cov: 32)
  • Exomes 𝑓: 0.026 (566 hom.)
• Consequence: GPX2 NM_002083.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.193
• Publications: 7 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=-0.82).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0186 (2826/152264) while in subpopulation NFE AF = 0.0289 (1966/68010). AF 95% confidence interval is 0.0278. There are 37 homozygotes in GnomAd4. There are 1359 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

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.222+19T>A		intron	N/A	NP_002074.2
	CHURC1-FNTB	NM_001202559.1		c.327+16406A>T		intron	N/A	NP_001189488.1	B4DL54
	CHURC1-FNTB	NM_001202558.2		c.6+18360A>T		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.222+19T>A		intron	N/A	ENSP00000374265.5	P18283
	CHURC1-FNTB	ENST00000549987.1	TSL:2	c.246+16406A>T		intron	N/A	ENSP00000447121.2	B4DL54
	GPX2	ENST00000553522.1	TSL:1	n.222+19T>A		intron	N/A	ENSP00000450991.1	G3V323

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2828 AN: 152146 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00497

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0298

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0289

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0185 AC: 4599 AN: 248564 AF XY: 0.0187

Gnomad AFR exome AF: 0.00368

Gnomad AMR exome AF: 0.00925

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0341

Gnomad NFE exome AF: 0.0272

Gnomad OTH exome AF: 0.0190

GnomAD4 exome AF: 0.0260 AC: 37798 AN: 1451820 Hom.: 566 Cov.: 29 AF XY: 0.0254 AC XY: 18366 AN XY: 722764

African (AFR) AF: 0.00357 AC: 119 AN: 33290

American (AMR) AF: 0.00960 AC: 429 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 355 AN: 26042

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39628

South Asian (SAS) AF: 0.00703 AC: 605 AN: 86032

European-Finnish (FIN) AF: 0.0337 AC: 1797 AN: 53382

Middle Eastern (MID) AF: 0.00424 AC: 22 AN: 5194

European-Non Finnish (NFE) AF: 0.0301 AC: 33219 AN: 1103510

Other (OTH) AF: 0.0208 AC: 1251 AN: 60038

GnomAD4 genome AF: 0.0186 AC: 2826 AN: 152264 Hom.: 37 Cov.: 32 AF XY: 0.0183 AC XY: 1359 AN XY: 74450

African (AFR) AF: 0.00491 AC: 204 AN: 41552

American (AMR) AF: 0.0133 AC: 203 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4820

European-Finnish (FIN) AF: 0.0298 AC: 316 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0289 AC: 1966 AN: 68010

Other (OTH) AF: 0.0132 AC: 28 AN: 2116

Alfa AF: 0.0239 Hom.: 12

Bravo AF: 0.0168

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.55
PhyloP100		-0.19
PromoterAI		0.0089	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800669; hg19: chr14-65409204;