Genetic Variant ENST00000549987.1:c.246+12924G>T (chr14-64939004-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000549987.1(CHURC1-FNTB):c.246+12924G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0906 in 156,886 control chromosomes in the GnomAD database, including 833 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 0.090 ( 799 hom., cov: 32)

Exomes 𝑓: 0.11 ( 34 hom. )

Consequence

CHURC1-FNTB
ENST00000549987.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.724

Publications

22 publications found

Variant links:

Genes affected

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-FNTB links:

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]

CHURC1 links:

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]

GPX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPX2	NM_002083.4 link	c.*484C>A		downstream_gene_variant		ENST00000389614.6	NP_002074.2	P18283

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHURC1-FNTB	ENST00000549987.1 link	c.246+12924G>T		intron_variant	Intron 3 of 13	2		ENSP00000447121.2		B4DL54
GPX2	ENST00000389614.6 link	c.*484C>A		downstream_gene_variant		1	NM_002083.4	ENSP00000374265.5		P18283

Frequencies

GnomAD3 genomes

AF:

0.0901

AC:

13701

AN:

152056

Hom.:

798

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0228

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.0869

Gnomad ASJ

AF:

0.0983

Gnomad EAS

AF:

0.0718

Gnomad SAS

AF:

0.0236

Gnomad FIN

AF:

0.174

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.124

Gnomad OTH

AF:

0.0755

GnomAD4 exome

AF:

0.108

AC:

508

AN:

4712

Hom.:

AF XY:

0.101

AC XY:

241

AN XY:

2388

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.0802

AC:

AN:

910

Ashkenazi Jewish (ASJ)

AF:

0.0577

AC:

AN:

East Asian (EAS)

AF:

0.116

AC:

AN:

198

South Asian (SAS)

AF:

0.0368

AC:

AN:

408

European-Finnish (FIN)

AF:

0.171

AC:

AN:

152

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.125

AC:

345

AN:

2754

Other (OTH)

AF:

0.128

AC:

AN:

180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0901

AC:

13704

AN:

152174

Hom.:

799

Cov.:

AF XY:

0.0917

AC XY:

6823

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0227

AC:

944

AN:

41520

American (AMR)

AF:

0.0871

AC:

1331

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0983

AC:

341

AN:

3470

East Asian (EAS)

AF:

0.0720

AC:

373

AN:

5184

South Asian (SAS)

AF:

0.0239

AC:

115

AN:

4818

European-Finnish (FIN)

AF:

0.174

AC:

1844

AN:

10582

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.124

AC:

8450

AN:

67996

Other (OTH)

AF:

0.0747

AC:

158

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

655

1310

1966

2621

3276

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.109

Hom.:

1650

Bravo

AF:

0.0825

Asia WGS

AF:

0.0590

AC:

204

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.6

(source)

DANN

Benign

0.70

PhyloP100

0.72

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over