7-16794972-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_006408.4(AGR2):c.442C>A(p.Arg148Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGR2 NM_006408.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

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]

ACMG classification

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 8 pathogenic changes around while only 1 benign (89%) in NM_006408.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGR2	NM_006408.4	c.442C>A	p.Arg148Ser	missense_variant	7/8	ENST00000419304.7
AGR2	XM_005249581.5	c.442C>A	p.Arg148Ser	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGR2	ENST00000419304.7	c.442C>A	p.Arg148Ser	missense_variant	7/8	1	NM_006408.4	P1
AGR2	ENST00000401412.5	c.442C>A	p.Arg148Ser	missense_variant	7/7	2
AGR2	ENST00000450569.5	c.232C>A	p.Arg78Ser	missense_variant	4/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251452 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2023

The c.442C>A (p.R148S) alteration is located in exon 7 (coding exon 6) of the AGR2 gene. This alteration results from a C to A substitution at nucleotide position 442, causing the arginine (R) at amino acid position 148 to be replaced by a serine (S). 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	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.11	T;T;T
Sift4G	Uncertain	0.052	T;D;D
Polyphen		0.35	B;.;.
Vest4		0.62
MutPred		0.44		Gain of methylation at R144 (P = 0.0736);.;Gain of methylation at R144 (P = 0.0736);
MVP		0.67
MPC		0.59
ClinPred		0.86	D
GERP RS		5.8
Varity_R		0.25
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: -36

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

Publications

LitVar

Other links and lift over

dbSNP: rs1169603250; hg19: chr7-16834596;