rs189270875

Positions:

• chr7-142752899-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_002769.5(PRSS1):​c.623G>C​(p.Gly208Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000219 in 1,614,144 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G208R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 37)
  • Exomes 𝑓: 0.00021 (3 hom.)
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:2
• Conservation: PhyloP100: 5.59

Genes affected

PRSS1 (HGNC:9475): (serine protease 1) This gene encodes a trypsinogen, which is a member of the trypsin family of serine proteases. This enzyme is secreted by the pancreas and cleaved to its active form in the small intestine. It is active on peptide linkages involving the carboxyl group of lysine or arginine. Mutations in this gene are associated with hereditary pancreatitis. This gene and several other trypsinogen genes are localized to the T cell receptor beta locus on chromosome 7. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020391077).
• BS2: High AC in GnomAd4 at 53 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRSS1	NM_002769.5	c.623G>C	p.Gly208Ala	missense_variant	5/5	ENST00000311737.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRSS1	ENST00000311737.12	c.623G>C	p.Gly208Ala	missense_variant	5/5	1	NM_002769.5	P1
PRSS1	ENST00000486171.5	c.665G>C	p.Gly222Ala	missense_variant	6/6	5
PRSS1	ENST00000492062.1	c.*27G>C		3_prime_UTR_variant	4/4	2
PRSS1	ENST00000463701.1	n.1087G>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152174 Hom.: 0 Cov.: 37

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00906

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000716 AC: 180 AN: 251472 Hom.: 0 AF XY: 0.000684 AC XY: 93 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00951

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000206 AC: 301 AN: 1461852 Hom.: 3 Cov.: 51 AF XY: 0.000216 AC XY: 157 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00678

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152292 Hom.: 0 Cov.: 37 AF XY: 0.000403 AC XY: 30 AN XY: 74468

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00908

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000336

ExAC AF: 0.000692 AC: 84

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary pancreatitis Pathogenic:2 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 29, 2023	The PRSS1 c.623G>C; p.Gly208Ala variant (rs189270875) is reported in the literature in multiple individuals affected with pancreatitis, some of whom carry additional pathogenic variants in the CFTR or SPINK1 genes (Cho 2016, Hegyi 2014, Keiles 2006, Lee 2015, Masamune 2014, Saito 2016, Xiao 2017, Zou 2018). However, this variant has also been reported in asymptomatic individuals (Hegyi 2014, Zou 2018). This variant is reported in ClinVar (Variation ID: 258802), and is found in the East Asian population with an allele frequency of 0.99% (197/19954 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.368). Functional analyses of the variant protein show normal autoactivation but a moderate reduction in secretion (Schnur 2014), which has been shown to cause ER stress and increase the risk of pancreatitis for other PRSS1 variants (Sahin-Toth 2017). While the increased prevalence in pancreatitis patients suggests that this variant may increase the risk for pancreatitis, due to conflicting information, the clinical significance of the p.Gly208Ala variant is uncertain at this time. References: Cho SM et al. PRSS1, SPINK1, CFTR, and CTRC Pathogenic Variants in Korean Patients With Idiopathic Pancreatitis. Ann Lab Med. 2016 Nov;36(6):555-60. PMID: 27578509. Hegyi E et al. Chronic pancreatitis associated with the p.G208A variant of PRSS1 gene in a European patient. JOP. 2014 Jan 10;15(1):49-52. PMID: 24413785. Keiles S and Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. Lee YJ et al. The PRSS1 c.623G>C (p.G208A) mutation is the most common PRSS1 mutation in Korean children with hereditary pancreatitis. Gut. 2015 Feb;64(2):359-60. PMID: 24780743. Masamune A et al. PRSS1 c.623G>C (p.G208A) variant is associated with pancreatitis in Japan. Gut. 2014 Feb;63(2):366. PMID: 23686146. Sahin-Toth M et al. Genetic risk in chronic pancreatitis: the misfolding-dependent pathway. Curr Opin Gastroenterol. 2017 Sep;33(5):390-395. PMID: 28650851. Saito N et al. Genetic Analysis of Japanese Children With Acute Recurrent and Chronic Pancreatitis. J Pediatr Gastroenterol Nutr. 2016 Oct;63(4):431-6. PMID: 27409067. Schnur A et al. Functional effects of 13 rare PRSS1 variants presumed to cause chronic pancreatitis. Gut. 2014 Feb;63(2):337-43. PMID: 23455445. Xiao Y et al. Targeted Gene Next-Generation Sequencing in Chinese Children with Chronic Pancreatitis and Acute Recurrent Pancreatitis. J Pediatr. 2017 Dec;191:158-163.e3. PMID: 29173301. Zou WB et al. SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis. Clin Transl Gastroenterol. 2018 Nov 12;9(11):204. PMID: 30420730. -
Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 13, 2016	proposed classification - variant undergoing re-assessment, contact laboratory -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 14, 2024	The p.G208A variant (also known as c.623G>C), located in coding exon 5 of the PRSS1 gene, results from a G to C substitution at nucleotide position 623. The glycine at codon 208 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in multiple individuals with pancreatitis, often with variants in other pancreatitis-associated genes (Hegyi E et al. JOP, 2014 Jan;15:49-52; Lee YJ et al. Gut, 2015 Feb;64:359-60; Cho SM et al. Ann Lab Med, 2016 Nov;36:555-60; Saito N et al. J Pediatr Gastroenterol Nutr, 2016 10;63:431-6). The variant was also significantly associated with idiopathic chronic pancreatitis in Japanese and Chinese cohorts (Masamune A et al. Gut, 2014 Feb;63:366; Zou WB et al. Clin Transl Gastroenterol, 2018 11;9:204). In one functional study, this alteration retained normal trypsin activity; however, it also resulted in reduced trypsinogen secretion (Schnúr A et al. Gut, 2014 Feb;63:337-43), which may be consistent with an alternate mechanism of disease pathogenesis. Based on data from gnomAD, the C allele has an overall frequency of 0.07% (202/282874) total alleles studied. The highest observed frequency was 0.99% (197/19954) of East Asian alleles. This amino acid position is well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, disease penetrance is expected to be variable. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	0.16
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Uncertain	0.56	D
MutationTaster	Benign	0.81	D;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-5.5	D;.;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.59
MVP		0.91
MPC		0.68
ClinPred		0.22	T
GERP RS		2.3
Varity_R		0.28
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs189270875; hg19: chr7-142460750;