7-16795011-G-C

Position:

• chr7-16795011-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_006408.4(AGR2):​c.403C>G​(p.Leu135Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGR2 NM_006408.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12

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 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.21695513).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGR2	NM_006408.4	c.403C>G	p.Leu135Val	missense_variant	7/8	ENST00000419304.7	NP_006399.1
AGR2	XM_005249581.5	c.403C>G	p.Leu135Val	missense_variant	7/8		XP_005249638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGR2	ENST00000419304.7	c.403C>G	p.Leu135Val	missense_variant	7/8	1	NM_006408.4	ENSP00000391490.2
AGR2	ENST00000401412.5	c.403C>G	p.Leu135Val	missense_variant	7/7	2		ENSP00000386025.1
AGR2	ENST00000450569.5	c.193C>G	p.Leu65Val	missense_variant	4/5	5		ENSP00000414806.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

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

Aug 08, 2023

The c.403C>G (p.L135V) alteration is located in exon 7 (coding exon 6) of the AGR2 gene. This alteration results from a C to G substitution at nucleotide position 403, causing the leucine (L) at amino acid position 135 to be replaced by a valine (V). 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	Uncertain	0.47
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;T
Eigen	Benign	-0.096
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.32	N;N;N
REVEL	Benign	0.090
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.064	T;T;T
Polyphen		0.012	B;.;.
Vest4		0.39
MutPred		0.64		Gain of catalytic residue at L135 (P = 0.2014);.;Gain of catalytic residue at L135 (P = 0.2014);
MVP		0.37
MPC		0.21
ClinPred		0.42	T
GERP RS		3.6
Varity_R		0.26
gMVP		0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-16834635;