11-57389117-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002728.6(PRG2):c.259C>G(p.Leu87Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: PRG2 NM_002728.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.73

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]

ACMG classification

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=0.050420135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRG2	NM_002728.6	c.259C>G	p.Leu87Val	missense_variant	3/6	ENST00000311862.10
PRG2	NM_001302926.2	c.259C>G	p.Leu87Val	missense_variant	3/6
PRG2	NM_001302927.2	c.259C>G	p.Leu87Val	missense_variant	3/6
PRG2	NM_001243245.3	c.259C>G	p.Leu87Val	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRG2	ENST00000311862.10	c.259C>G	p.Leu87Val	missense_variant	3/6	1	NM_002728.6	P1
PRG2	ENST00000525955.1	c.259C>G	p.Leu87Val	missense_variant	3/6	2		P1
PRG2	ENST00000533605.5	c.259C>G	p.Leu87Val	missense_variant	3/6	5
PRG2	ENST00000530105.1	n.305C>G		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251496 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000200 AC: 292 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.000176 AC XY: 128 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000256

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74346

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000247 Hom.: 0

Bravo AF: 0.000155

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000164

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2022

The c.259C>G (p.L87V) alteration is located in exon 3 (coding exon 2) of the PRG2 gene. This alteration results from a C to G substitution at nucleotide position 259, causing the leucine (L) at amino acid position 87 to be replaced by a valine (V). 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	0.074
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.010
Dann	Uncertain	0.98
DEOGEN2	Benign	0.12	T;.;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.010	N
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.050	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N;N;N;.
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.77	N;N;N;N
REVEL	Benign	0.0080
Sift	Benign	0.53	T;T;T;D
Sift4G	Benign	0.75	T;T;T;T
Polyphen		0.11	B;.;B;.
Vest4		0.070
MVP		0.19
MPC		0.051
ClinPred		0.025	T
GERP RS		-9.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.033
gMVP		0.11

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

Other links and lift over

dbSNP: rs144421947; hg19: chr11-57156590;