chr7-142752899-G-C
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting
The NM_002769.5(PRSS1):āc.623G>Cā(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
Consequence
NM_002769.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
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: 53AN: 152174Hom.: 0 Cov.: 37
GnomAD3 exomes AF: 0.000716 AC: 180AN: 251472Hom.: 0 AF XY: 0.000684 AC XY: 93AN XY: 135908
GnomAD4 exome AF: 0.000206 AC: 301AN: 1461852Hom.: 3 Cov.: 51 AF XY: 0.000216 AC XY: 157AN XY: 727226
GnomAD4 genome AF: 0.000348 AC: 53AN: 152292Hom.: 0 Cov.: 37 AF XY: 0.000403 AC XY: 30AN XY: 74468
ClinVar
Submissions by phenotype
Hereditary pancreatitis Pathogenic:2Uncertain:2Benign: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 | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at