rs6842

Positions:

• chr7-16794973-A-C
• chr7-16794973-A-G
• chr7-16794973-A-T

Variant summary

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

The NM_006408.4(AGR2):​c.441T>G​(p.Asn147Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGR2 NM_006408.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.278

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 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	c.441T>G	p.Asn147Lys	missense_variant	7/8	ENST00000419304.7	NP_006399.1
AGR2	XM_005249581.5	c.441T>G	p.Asn147Lys	missense_variant	7/8		XP_005249638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGR2	ENST00000419304.7	c.441T>G	p.Asn147Lys	missense_variant	7/8	1	NM_006408.4	ENSP00000391490	P1
AGR2	ENST00000401412.5	c.441T>G	p.Asn147Lys	missense_variant	7/7	2		ENSP00000386025
AGR2	ENST00000450569.5	c.231T>G	p.Asn77Lys	missense_variant	4/5	5		ENSP00000414806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 59

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	D;.;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.85	T;D;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.1	D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.015	B;.;.
Vest4		0.78
MutPred		0.75		Gain of ubiquitination at N147 (P = 0.0289);.;Gain of ubiquitination at N147 (P = 0.0289);
MVP		0.46
MPC		0.21
ClinPred		1.0	D
GERP RS		-7.0
Varity_R		0.83
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs6842; hg19: chr7-16834597;