Variant 7-16797693-T-C 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.332A>G(p.Tyr111Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,598 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AGR2
NM_006408.4 missense, splice_region

Scores

Splicing: ADA: 0.9178

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.45

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.332A>G	p.Tyr111Cys	missense_variant, splice_region_variant	6/8	ENST00000419304.7	NP_006399.1	O95994Q4JM46
AGR2	XM_005249581.5 link	c.332A>G	p.Tyr111Cys	missense_variant, splice_region_variant	6/8		XP_005249638.1	O95994Q4JM46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AGR2	ENST00000419304.7 link	c.332A>G	p.Tyr111Cys	missense_variant, splice_region_variant	6/8	1	NM_006408.4	ENSP00000391490.2	O95994
AGR2	ENST00000401412.5 link	c.332A>G	p.Tyr111Cys	missense_variant, splice_region_variant	6/7	2		ENSP00000386025.1	B5MC07
AGR2	ENST00000412973.1 link	c.332A>G	p.Tyr111Cys	missense_variant, splice_region_variant	7/7	5		ENSP00000411969.1	C9J3E2
AGR2	ENST00000450569.5 link	c.122A>G	p.Tyr41Cys	missense_variant, splice_region_variant	3/5	5		ENSP00000414806.1	H7C3Z9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460598

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726568

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Respiratory infections, recurrent, and failure to thrive with or without diarrhea

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;.;T;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Benign

0.046

MetaRNN

Uncertain

0.71

D;D;D;D

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.4

M;.;.;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.2

D;D;D;D

REVEL

Benign

0.29

Sift

Uncertain

0.0080

D;D;D;D

Sift4G

Uncertain

0.020

D;T;T;.

Polyphen

1.0

D;.;.;.

Vest4

0.79

MutPred

0.43

Gain of catalytic residue at T113 (P = 0.0575);.;Gain of catalytic residue at T113 (P = 0.0575);Gain of catalytic residue at T113 (P = 0.0575);

MVP

0.73

MPC

0.78

ClinPred

0.96

GERP RS

6.0

Varity_R

0.41

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.92

dbscSNV1_RF

Pathogenic

0.80

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over