16-20311266-C-A

Variant names:

• chr16-20311266-C-A
• rs150906566
• NM_001502.4:c.1562G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001502.4(GP2):​c.1562G>T​(p.Trp521Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000504 in 1,606,328 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 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: GP2 NM_001502.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

Genes affected

GP2 (HGNC:4441): (glycoprotein 2) This gene encodes an integral membrane protein that is secreted from intracellular zymogen granules and associates with the plasma membrane via glycosylphosphatidylinositol (GPI) linkage. The encoded protein binds pathogens such as enterobacteria, thereby playing an important role in the innate immune response. The C-terminus of this protein is related to the C-terminus of the protein encoded by the neighboring gene, uromodulin (UMOD). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1391815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP2	NM_001502.4	c.1562G>T	p.Trp521Leu	missense_variant	Exon 11 of 11	ENST00000302555.10	NP_001493.2
GP2	NM_001007240.3	c.1571G>T	p.Trp524Leu	missense_variant	Exon 12 of 12		NP_001007241.2
GP2	NM_001007241.3	c.1130G>T	p.Trp377Leu	missense_variant	Exon 11 of 11		NP_001007242.2
GP2	NM_001007242.3	c.1121G>T	p.Trp374Leu	missense_variant	Exon 10 of 10		NP_001007243.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP2	ENST00000302555.10	c.1562G>T	p.Trp521Leu	missense_variant	Exon 11 of 11	1	NM_001502.4	ENSP00000304044.6
GP2	ENST00000381362.8	c.1571G>T	p.Trp524Leu	missense_variant	Exon 12 of 12	1		ENSP00000370767.4
GP2	ENST00000381360.9	c.1130G>T	p.Trp377Leu	missense_variant	Exon 11 of 11	1		ENSP00000370765.5
GP2	ENST00000341642.9	c.1121G>T	p.Trp374Leu	missense_variant	Exon 10 of 10	1		ENSP00000343861.5

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00113

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000717 AC: 18 AN: 251118 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135726

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000213 AC: 31 AN: 1454036 Hom.: 0 Cov.: 27 AF XY: 0.0000193 AC XY: 14 AN XY: 724034

Gnomad4 AFR exome AF: 0.000631

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000666

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74478

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000387 Hom.: 0

Bravo AF: 0.000389

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1571G>T (p.W524L) alteration is located in exon 12 (coding exon 11) of the GP2 gene. This alteration results from a G to T substitution at nucleotide position 1571, causing the tryptophan (W) at amino acid position 524 to be replaced by a leucine (L). 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	0.14
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	.;.;D;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.6	.;.;M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.013	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.78	P;P;P;.
Vest4		0.43
MVP		0.73
MPC		0.39
ClinPred		0.19	T
GERP RS		5.1
Varity_R		0.48
gMVP		0.66

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: rs150906566; hg19: chr16-20322588;