Genetic Variant PRSS22:p.Trp213Cys (chr16-2853943-C-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_022119.4(PRSS22):c.639G>C(p.Trp213Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000833 in 1,614,092 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00086 ( 5 hom. )

Consequence

PRSS22
NM_022119.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.674

Variant links:

Genes affected

PRSS22 (HGNC:14368): (serine protease 22) This gene encodes a member of the trypsin family of serine proteases. The enzyme is expressed in the airways in a developmentally regulated manner. The gene is part of a cluster of serine protease genes on chromosome 16. [provided by RefSeq, Jul 2008]

PRSS22 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.28291118).

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS22	NM_022119.4 link	c.639G>C	p.Trp213Cys	missense_variant	Exon 5 of 6	ENST00000161006.8	NP_071402.1	Q9GZN4
PRSS22	XM_047434451.1 link	c.426G>C	p.Trp142Cys	missense_variant	Exon 3 of 4		XP_047290407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS22	ENST00000161006.8 link	c.639G>C	p.Trp213Cys	missense_variant	Exon 5 of 6	1	NM_022119.4	ENSP00000161006.3		Q9GZN4

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000744

AC:

187

AN:

251450

Hom.:

AF XY:

0.000765

AC XY:

104

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.000861

AC:

1259

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000876

AC XY:

637

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00137

Gnomad4 FIN exome

AF:

0.000393

Gnomad4 NFE exome

AF:

0.000929

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.000565

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000620

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.000574

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000766

AC:

EpiCase

AF:

0.00125

EpiControl

AF:

0.000830

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.639G>C (p.W213C) alteration is located in exon 5 (coding exon 5) of the PRSS22 gene. This alteration results from a G to C substitution at nucleotide position 639, causing the tryptophan (W) at amino acid position 213 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Benign

0.37

T;.

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.52

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.28

T;T

MetaSVM

Uncertain

0.00030

MutationAssessor

Benign

1.2

L;.

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.3

N;.

REVEL

Uncertain

0.56

Sift

Benign

0.086

T;.

Sift4G

Benign

0.081

T;T

Polyphen

1.0

D;.

Vest4

0.52

MutPred

0.60

Loss of catalytic residue at L211 (P = 0.0029);.;

MVP

0.94

MPC

1.3

ClinPred

0.026

GERP RS

3.3

Varity_R

0.17

gMVP

0.94

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over