7-142751933-C-G

Variant names:

• chr7-142751933-C-G
• rs606231348
• NM_002769.5:c.360C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_002769.5(PRSS1):​c.360C>G​(p.Asn120Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N120N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 33 uncertain in NM_002769.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS1	NM_002769.5	c.360C>G	p.Asn120Lys	missense_variant	Exon 3 of 5	ENST00000311737.12	NP_002760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12	c.360C>G	p.Asn120Lys	missense_variant	Exon 3 of 5	1	NM_002769.5	ENSP00000308720.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 62

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	12
DANN	Benign	0.89
DEOGEN2	Uncertain	0.76	.;.;D;D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.074	N
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.9	.;.;L;.
PhyloP100		0.24
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.9	D;.;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.66
MutPred		0.70		Gain of methylation at N134 (P = 0.0145);.;.;.;
MVP		0.67
MPC		0.71
ClinPred		0.97	D
GERP RS		-6.6
Varity_R		0.47
gMVP		0.66
Mutation Taster		=77/23	polymorphism

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: rs606231348; hg19: chr7-142459784;