Genetic Variant GPC2:p.Leu408Val (chr7-100171627-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_152742.3(GPC2):c.1222C>G(p.Leu408Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000159 in 1,380,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

GPC2
NM_152742.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.13

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC2	NM_152742.3 link	c.1222C>G	p.Leu408Val	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.1222C>G	p.Leu408Val	missense_variant	Exon 8 of 10	1	NM_152742.3	ENSP00000292377.2	Q8N158
GPC2	ENST00000486702.1 link	n.331C>G		non_coding_transcript_exon_variant	Exon 3 of 4	3
GPC2	ENST00000490629.5 link	n.*24C>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000725

AC:

AN:

137910

Hom.:

AF XY:

0.0000128

AC XY:

AN XY:

78352

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000162

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000159

AC:

AN:

1380724

Hom.:

Cov.:

AF XY:

0.0000161

AC XY:

AN XY:

684304

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000203

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000911

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1222C>G (p.L408V) alteration is located in exon 8 (coding exon 8) of the GPC2 gene. This alteration results from a C to G substitution at nucleotide position 1222, causing the leucine (L) at amino acid position 408 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

0.20

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

Eigen

Benign

0.19

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.51

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.92

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.35

Sift

Uncertain

0.0020

Sift4G

Benign

0.099

Polyphen

0.59

Vest4

0.49

MutPred

0.88

Gain of MoRF binding (P = 0.0994);

MVP

0.43

MPC

1.7

ClinPred

0.62

GERP RS

4.3

Varity_R

0.44

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

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