7-142774035-G-A

Variant names:

• chr7-142774035-G-A
• rs61734659
• NM_002770.4:c.571G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002770.4(PRSS2):​c.571G>A​(p.Gly191Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 1,596,326 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as protective (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (0 hom., cov: 40)
  • Exomes 𝑓: 0.020 (1 hom.)
• Consequence: PRSS2 NM_002770.4 missense
• Clinical Significance: protective no assertion criteria provided B:1
• Conservation: PhyloP100: 9.89
• Publications: 37 publications found

Genes affected

PRSS2 (HGNC:9483): (serine protease 2) This gene belongs to the trypsin family of serine proteases and encodes anionic trypsinogen. It is part of a cluster of trypsinogen genes that are located within the T cell receptor beta locus. Enzymes of this family cleave peptide bonds that follow lysine or arginine residues. This protein is found at high levels in pancreatic juice and its upregulation is a characteristic feature of pancreatitis. This protein has also been found to activate pro-urokinase in ovarian tumors, suggesting a function in tumor invasion. In addition, this enzyme is able to cleave across the type II collagen triple helix in rheumatoid arthritis synovitis tissue, potentially participating in the degradation of type II collagen-rich cartilage matrix. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jan 2015]

TRB (HGNC:12155):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Variant has high frequency in the NFE (0.0203) population. However there is too low homozygotes in high coverage region: (expected more than 146, got 1).
• BP4: Computational evidence support a benign effect (MetaRNN=0.042755485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS2	NM_002770.4	c.571G>A	p.Gly191Arg	missense_variant	Exon 4 of 5	ENST00000539842.6	NP_002761.1
PRSS2	NM_001303414.2	c.613G>A	p.Gly205Arg	missense_variant	Exon 5 of 6		NP_001290343.1
PRSS2	NR_130149.2	n.510G>A		non_coding_transcript_exon_variant	Exon 4 of 5
TRB		n.142774035G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS2	ENST00000539842.6	c.571G>A	p.Gly191Arg	missense_variant	Exon 4 of 5	1	NM_002770.4	ENSP00000488338.1
PRSS2	ENST00000633969.1	c.613G>A	p.Gly205Arg	missense_variant	Exon 5 of 6	1		ENSP00000488437.1
PRSS2	ENST00000632998.1	c.571G>A	p.Gly191Arg	missense_variant	Exon 4 of 5	1		ENSP00000488789.1
PRSS2	ENST00000618750.2	n.421G>A		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2205 AN: 151790 Hom.: 0 Cov.: 40

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.0606

Gnomad AMR AF: 0.00958

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.00892

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0193

Gnomad OTH AF: 0.0130

GnomAD4 exome AF: 0.0197 AC: 28386 AN: 1444418 Hom.: 1 Cov.: 42 AF XY: 0.0195 AC XY: 13997 AN XY: 719610

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00350 AC: 116 AN: 33130

American (AMR) AF: 0.00855 AC: 382 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0229 AC: 596 AN: 26032

East Asian (EAS) AF: 0.0204 AC: 808 AN: 39596

South Asian (SAS) AF: 0.00876 AC: 752 AN: 85832

European-Finnish (FIN) AF: 0.0359 AC: 1916 AN: 53374

Middle Eastern (MID) AF: 0.00662 AC: 38 AN: 5744

European-Non Finnish (NFE) AF: 0.0206 AC: 22547 AN: 1096208

Other (OTH) AF: 0.0206 AC: 1231 AN: 59800

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0145 AC: 2204 AN: 151908 Hom.: 0 Cov.: 40 AF XY: 0.0149 AC XY: 1108 AN XY: 74260

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00318 AC: 132 AN: 41524

American (AMR) AF: 0.00956 AC: 146 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0188 AC: 65 AN: 3464

East Asian (EAS) AF: 0.0105 AC: 54 AN: 5166

South Asian (SAS) AF: 0.00893 AC: 43 AN: 4814

European-Finnish (FIN) AF: 0.0353 AC: 373 AN: 10552

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0193 AC: 1306 AN: 67820

Other (OTH) AF: 0.0128 AC: 27 AN: 2102

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0149 Hom.: 0

ClinVar

Significance: protective

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Pancreatitis, chronic, protection against Benign:1

Jun 01, 2006

OMIM

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CADD	Uncertain	23
DEOGEN2	Benign	0.098	T;D;.;D
LIST_S2	Uncertain	0.95	D;D;D;.
MetaRNN	Benign	0.043	T;T;T;T
PhyloP100		9.9
Sift4G	Uncertain	0.019	D;D;D;D
Vest4		0.82
gMVP		0.77

Splicing

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

Other links and lift over

dbSNP: rs61734659; hg19: -;