11-57389272-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002728.6(PRG2):c.104T>A(p.Leu35Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,818 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

PRG2
NM_002728.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.646

Variant links:

Genes affected

PRG2 (HGNC:9362): (proteoglycan 2, pro eosinophil major basic protein) The protein encoded by this gene is the predominant constituent of the crystalline core of the eosinophil granule. High levels of the proform of this protein are also present in placenta and pregnancy serum, where it exists as a complex with several other proteins including pregnancy-associated plasma protein A (PAPPA), angiotensinogen (AGT), and C3dg. This protein may be involved in antiparasitic defense mechanisms as a cytotoxin and helminthotoxin, and in immune hypersensitivity reactions. The encoded protein contains a peptide that displays potent antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, and fungi. It is directly implicated in epithelial cell damage, exfoliation, and bronchospasm in allergic diseases. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2014]

PRG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.027194679).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PRG2	NM_002728.6 linkuse as main transcript	c.104T>A	p.Leu35Gln	missense_variant	3/6	ENST00000311862.10
PRG2	NM_001302926.2 linkuse as main transcript	c.104T>A	p.Leu35Gln	missense_variant	3/6
PRG2	NM_001302927.2 linkuse as main transcript	c.104T>A	p.Leu35Gln	missense_variant	3/6
PRG2	NM_001243245.3 linkuse as main transcript	c.104T>A	p.Leu35Gln	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRG2	ENST00000311862.10 linkuse as main transcript	c.104T>A	p.Leu35Gln	missense_variant	3/6	1	NM_002728.6	P1	P13727-1
PRG2	ENST00000525955.1 linkuse as main transcript	c.104T>A	p.Leu35Gln	missense_variant	3/6	2		P1	P13727-1
PRG2	ENST00000533605.5 linkuse as main transcript	c.104T>A	p.Leu35Gln	missense_variant	3/6	5			P13727-2
PRG2	ENST00000530105.1 linkuse as main transcript	n.150T>A		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000995

AC:

AN:

251176

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461672

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00157

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000137

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2021

The c.104T>A (p.L35Q) alteration is located in exon 3 (coding exon 2) of the PRG2 gene. This alteration results from a T to A substitution at nucleotide position 104, causing the leucine (L) at amino acid position 35 to be replaced by a glutamine (Q). 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

Benign

0.079

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.41

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.53

D;.;D;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.028

M_CAP

Benign

0.0090

MetaRNN

Benign

0.027

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.3

M;M;M;.

MutationTaster

Benign

1.0

N;N;N

PROVEAN

Uncertain

-3.2

D;D;D;N

REVEL

Benign

0.055

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Benign

0.067

T;T;T;D

Polyphen

1.0

D;.;D;.

Vest4

0.46

MVP

0.49

MPC

0.33

ClinPred

0.25

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.29

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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