chr2-240462383-G-C

Variant names:

• chr2-240462383-G-C
• rs767152299
• NM_002081.3:c.518G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002081.3(GPC1):​c.518G>C​(p.Arg173Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R173H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GPC1 NM_002081.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54
• Publications: 0 publications found

Genes affected

GPC1 (HGNC:4449): (glypican 1) Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002081.3. 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
	GPC1	NM_002081.3	MANE Select	c.518G>C	p.Arg173Pro	missense	Exon 3 of 9	NP_002072.2	A0A384NPH9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC1	ENST00000264039.7	TSL:1 MANE Select	c.518G>C	p.Arg173Pro	missense	Exon 3 of 9	ENSP00000264039.2	P35052-1
	GPC1	ENST00000495100.1	TSL:1	n.1195G>C		non_coding_transcript_exon	Exon 2 of 7
	GPC1	ENST00000943307.1		c.674G>C	p.Arg225Pro	missense	Exon 4 of 10	ENSP00000613366.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		1.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.57	P
Vest4		0.77
MutPred		0.78		Gain of catalytic residue at R173 (P = 0.0685)
MVP		0.90
MPC		0.76
ClinPred		0.98	D
GERP RS		2.2
Varity_R		0.96
gMVP		0.86
Mutation Taster		=30/70	disease causing

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: rs767152299; hg19: chr2-241401800;