11-57387789-G-A

Variant names:

• chr11-57387789-G-A
• rs374486751
• NM_002728.6:c.575C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002728.6(PRG2):​c.575C>T​(p.Ser192Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000486 in 1,440,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: PRG2 NM_002728.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -7.60
• Publications: 0 publications found

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]

ENSG00000254979 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045235515).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002728.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRG2	NM_002728.6	MANE Select	c.575C>T	p.Ser192Phe	missense	Exon 5 of 6	NP_002719.3
	PRG2	NM_001302926.2		c.575C>T	p.Ser192Phe	missense	Exon 5 of 6	NP_001289855.1	P13727-1
	PRG2	NM_001302927.2		c.575C>T	p.Ser192Phe	missense	Exon 5 of 6	NP_001289856.1	P13727-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRG2	ENST00000311862.10	TSL:1 MANE Select	c.575C>T	p.Ser192Phe	missense	Exon 5 of 6	ENSP00000312134.5	P13727-1
	PRG2	ENST00000525955.1	TSL:2	c.575C>T	p.Ser192Phe	missense	Exon 5 of 6	ENSP00000433016.1	P13727-1
	PRG2	ENST00000886024.1		c.575C>T	p.Ser192Phe	missense	Exon 5 of 6	ENSP00000556083.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000468 AC: 1 AN: 213678 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000336

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000486 AC: 7 AN: 1440590 Hom.: 0 Cov.: 30 AF XY: 0.00000280 AC XY: 2 AN XY: 714286

African (AFR) AF: 0.00 AC: 0 AN: 33340

American (AMR) AF: 0.0000246 AC: 1 AN: 40724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25476

East Asian (EAS) AF: 0.00 AC: 0 AN: 39026

South Asian (SAS) AF: 0.00 AC: 0 AN: 82322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000454 AC: 5 AN: 1102410

Other (OTH) AF: 0.0000168 AC: 1 AN: 59694

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.0020
DANN	Benign	0.76
DEOGEN2	Benign	0.18	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.28	N
PhyloP100		-7.6
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.060
Sift	Benign	0.75	T
Sift4G	Benign	0.72	T
Polyphen		0.0010	B
Vest4		0.20
MVP		0.099
MPC		0.051
ClinPred		0.050	T
GERP RS		-9.8
Varity_R		0.38
gMVP		0.26
Mutation Taster		=98/2	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: rs374486751; hg19: chr11-57155262; COSMIC: COSV100314998; COSMIC: COSV100314998;