Genetic Variant GP2:p.Val301Ile (chr16-20319726-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_001502.4(GP2):c.901G>A(p.Val301Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,611,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

GP2
NM_001502.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.04

Variant links:

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]

GP2 links:

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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=0.026813805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP2	NM_001502.4 link	c.901G>A	p.Val301Ile	missense_variant	Exon 6 of 11	ENST00000302555.10	NP_001493.2	P55259-3Q68D34B7Z1G2
GP2	NM_001007240.3 link	c.910G>A	p.Val304Ile	missense_variant	Exon 7 of 12		NP_001007241.2	P55259-1B7Z1G2
GP2	NM_001007241.3 link	c.469G>A	p.Val157Ile	missense_variant	Exon 6 of 11		NP_001007242.2	B7Z1G2
GP2	NM_001007242.3 link	c.460G>A	p.Val154Ile	missense_variant	Exon 5 of 10		NP_001007243.2	B7Z1G2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP2	ENST00000302555.10 link	c.901G>A	p.Val301Ile	missense_variant	Exon 6 of 11	1	NM_001502.4	ENSP00000304044.6		P55259-3

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000479

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251394

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.000923

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:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1459614

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726272

show subpopulations

Gnomad4 AFR exome

AF:

0.000718

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000190

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.00

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:

0.000474

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.000189

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.910G>A (p.V304I) alteration is located in exon 7 (coding exon 6) of the GP2 gene. This alteration results from a G to A substitution at nucleotide position 910, causing the valine (V) at amino acid position 304 to be replaced by an isoleucine (I). 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

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

.;.;T;.

Eigen

Benign

-0.060

Eigen_PC

Benign

-0.071

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.86

D;D;D;D

M_CAP

Benign

0.031

MetaRNN

Benign

0.027

T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.2

.;.;M;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.60

N;N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.059

T;T;T;T

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.57

P;B;B;.

Vest4

0.14

MVP

0.34

MPC

0.18

ClinPred

0.023

GERP RS

3.3

Varity_R

0.047

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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