Variant chr7-16801669-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_006408.4(AGR2):c.128C>T(p.Thr43Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

AGR2
NM_006408.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.67

Variant links:

Genes affected

AGR2 (HGNC:328): (anterior gradient 2, protein disulphide isomerase family member) This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, a catalytically active thioredoxin domain, and a C-terminal ER-retention sequence. This protein plays a role in cell migration, cellular transformation and metastasis and is as a p53 inhibitor. As an ER-localized molecular chaperone, it plays a role in the folding, trafficking, and assembly of cysteine-rich transmembrane receptors and the cysteine-rich intestinal gylcoprotein mucin. This gene has been implicated in inflammatory bowel disease and cancer progression. [provided by RefSeq, Mar 2017]

AGR2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a chain Anterior gradient protein 2 homolog (size 154) in uniprot entity AGR2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_006408.4

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGR2	NM_006408.4 link	c.128C>T	p.Thr43Ile	missense_variant	2/8	ENST00000419304.7	NP_006399.1	O95994Q4JM46
AGR2	XM_005249581.5 link	c.128C>T	p.Thr43Ile	missense_variant	2/8		XP_005249638.1	O95994Q4JM46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGR2	ENST00000419304.7 link	c.128C>T	p.Thr43Ile	missense_variant	2/8	1	NM_006408.4	ENSP00000391490.2		O95994

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251228

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 03, 2024

The c.128C>T (p.T43I) alteration is located in exon 2 (coding exon 1) of the AGR2 gene. This alteration results from a C to T substitution at nucleotide position 128, causing the threonine (T) at amino acid position 43 to be replaced by an isoleucine (I). 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

0.96

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

D;T;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.57

D;D;D

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.5

M;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0040

D;D;.

Polyphen

0.94

P;.;.

Vest4

0.58

MutPred

0.27

Loss of disorder (P = 0.0295);Loss of disorder (P = 0.0295);Loss of disorder (P = 0.0295);

MVP

0.59

MPC

0.47

ClinPred

0.98

GERP RS

5.8

Varity_R

0.44

gMVP

0.60

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over