NM_002769.5:c.681A>G

Variant names:

• chr7-142752957-A-G
• rs780015944
• NM_002769.5:c.681A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_002769.5(PRSS1):​c.681A>G​(p.Gly227Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,612,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G227G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: PRSS1 NM_002769.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.49
• Publications: 0 publications found

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]

PRSS1 Gene-Disease associations (from GenCC):

• hereditary chronic pancreatitis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, PanelApp Australia, Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

TRB (HGNC:12155):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 7-142752957-A-G is Benign according to our data. Variant chr7-142752957-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 459186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.49 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 13 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002769.5. 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
	PRSS1	NM_002769.5	MANE Select	c.681A>G	p.Gly227Gly	synonymous	Exon 5 of 5	NP_002760.1
	PRSS1	NR_172947.1		n.623A>G		non_coding_transcript_exon	Exon 5 of 5
	PRSS1	NR_172948.1		n.620A>G		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS1	ENST00000311737.12	TSL:1 MANE Select	c.681A>G	p.Gly227Gly	synonymous	Exon 5 of 5	ENSP00000308720.7
	PRSS1	ENST00000486171.5	TSL:5	c.723A>G	p.Gly241Gly	synonymous	Exon 6 of 6	ENSP00000417854.1
	PRSS1	ENST00000463701.1	TSL:2	n.1145A>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0000265 AC: 4 AN: 151078 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251480 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461848 Hom.: 0 Cov.: 50 AF XY: 0.0000124 AC XY: 9 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000265 AC: 4 AN: 151078 Hom.: 0 Cov.: 28 AF XY: 0.0000135 AC XY: 1 AN XY: 73802

African (AFR) AF: 0.0000244 AC: 1 AN: 40992

American (AMR) AF: 0.00 AC: 0 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67732

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.0000474 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary pancreatitis (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.7
DANN	Benign	0.57
PhyloP100		-5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs780015944; hg19: chr7-142460808;