7-16794973-A-G

Variant names:

• chr7-16794973-A-G
• rs6842
• NM_006408.4:c.441T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_006408.4(AGR2):​c.441T>C​(p.Asn147Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 1,613,576 control chromosomes in the GnomAD database, including 182,388 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.38 (12741 hom., cov: 33)
  • Exomes 𝑓: 0.48 (169647 hom.)
• Consequence: AGR2 NM_006408.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.278
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• respiratory infections, recurrent, and failure to thrive with or without diarrhea

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP7: Synonymous conserved (PhyloP=0.278 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006408.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGR2	NM_006408.4	MANE Select	c.441T>C	p.Asn147Asn	synonymous	Exon 7 of 8	NP_006399.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGR2	ENST00000419304.7	TSL:1 MANE Select	c.441T>C	p.Asn147Asn	synonymous	Exon 7 of 8	ENSP00000391490.2
	AGR2	ENST00000401412.5	TSL:2	c.441T>C	p.Asn147Asn	synonymous	Exon 7 of 7	ENSP00000386025.1
	AGR2	ENST00000450569.5	TSL:5	c.231T>C	p.Asn77Asn	synonymous	Exon 4 of 5	ENSP00000414806.1

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57855 AN: 152078 Hom.: 12737 Cov.: 33

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.464

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.418

GnomAD2 exomes AF: 0.433 AC: 108759 AN: 251314 AF XY: 0.443

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.437

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.291

Gnomad FIN exome AF: 0.379

Gnomad NFE exome AF: 0.493

Gnomad OTH exome AF: 0.471

GnomAD4 exome AF: 0.477 AC: 696554 AN: 1461380 Hom.: 169647 Cov.: 59 AF XY: 0.478 AC XY: 347620 AN XY: 726990

African (AFR) AF: 0.138 AC: 4613 AN: 33476

American (AMR) AF: 0.445 AC: 19903 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 11892 AN: 26132

East Asian (EAS) AF: 0.313 AC: 12413 AN: 39684

South Asian (SAS) AF: 0.466 AC: 40191 AN: 86250

European-Finnish (FIN) AF: 0.383 AC: 20448 AN: 53412

Middle Eastern (MID) AF: 0.537 AC: 3100 AN: 5768

European-Non Finnish (NFE) AF: 0.500 AC: 556086 AN: 1111566

Other (OTH) AF: 0.462 AC: 27908 AN: 60374

GnomAD4 genome AF: 0.380 AC: 57875 AN: 152196 Hom.: 12741 Cov.: 33 AF XY: 0.378 AC XY: 28092 AN XY: 74414

African (AFR) AF: 0.153 AC: 6343 AN: 41548

American (AMR) AF: 0.464 AC: 7100 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 1611 AN: 3470

East Asian (EAS) AF: 0.300 AC: 1553 AN: 5182

South Asian (SAS) AF: 0.436 AC: 2105 AN: 4832

European-Finnish (FIN) AF: 0.378 AC: 3998 AN: 10586

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.494 AC: 33586 AN: 67982

Other (OTH) AF: 0.416 AC: 877 AN: 2108

Alfa AF: 0.458 Hom.: 21743

Bravo AF: 0.374

Asia WGS AF: 0.360 AC: 1254 AN: 3478

EpiCase AF: 0.498

EpiControl AF: 0.510

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.6
DANN	Benign	0.60
PhyloP100		0.28
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6842; hg19: chr7-16834597; COSMIC: COSV68596303; COSMIC: COSV68596303;