Genetic Variant GPC2:p.Ala427Val (chr7-100171569-G-A) – 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_152742.3(GPC2):c.1280C>T(p.Ala427Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000767 in 1,494,862 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00080 ( 1 hom. )

Consequence

GPC2
NM_152742.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.558

Variant links:

Genes affected

GPC2 (HGNC:4450): (glypican 2) Predicted to be involved in several processes, including positive regulation of neuron projection development; regulation of protein localization to membrane; and smoothened signaling pathway. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

GPC2 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=0.036485106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC2	NM_152742.3 link	c.1280C>T	p.Ala427Val	missense_variant	Exon 8 of 10	ENST00000292377.4	NP_689955.1	Q8N158

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GPC2	ENST00000292377.4 link	c.1280C>T	p.Ala427Val	missense_variant	Exon 8 of 10	1	NM_152742.3	ENSP00000292377.2	Q8N158
GPC2	ENST00000486702.1 link	n.389C>T		non_coding_transcript_exon_variant	Exon 3 of 4	3
GPC2	ENST00000490629.5 link	n.*82C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000721

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000412

AC:

AN:

104468

Hom.:

AF XY:

0.000448

AC XY:

AN XY:

60226

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000170

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000172

Gnomad NFE exome

AF:

0.000843

Gnomad OTH exome

AF:

0.000368

GnomAD4 exome

AF:

0.000804

AC:

1079

AN:

1342792

Hom.:

Cov.:

AF XY:

0.000755

AC XY:

501

AN XY:

663944

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.000276

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000177

Gnomad4 NFE exome

AF:

0.000977

Gnomad4 OTH exome

AF:

0.000360

GnomAD4 genome

AF:

0.000447

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.000721

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000539

Hom.:

Bravo

AF:

0.000510

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000326

AC:

ExAC

AF:

0.000243

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1280C>T (p.A427V) alteration is located in exon 8 (coding exon 8) of the GPC2 gene. This alteration results from a C to T substitution at nucleotide position 1280, causing the alanine (A) at amino acid position 427 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

0.091

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.92

REVEL

Benign

0.065

Sift

Benign

0.070

Sift4G

Benign

0.28

Polyphen

0.66

Vest4

0.23

MVP

0.26

MPC

1.5

ClinPred

0.052

GERP RS

2.4

Varity_R

0.059

gMVP

0.15

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

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