13-93830255-G-C

Variant names:

• chr13-93830255-G-C
• NM_005708.5:c.421G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005708.5(GPC6):​c.421G>C​(p.Asp141His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GPC6 NM_005708.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.13

Genes affected

GPC6 (HGNC:4454): (glypican 6) The glypicans comprise a family of glycosylphosphatidylinositol-anchored heparan sulfate proteoglycans, and they have been implicated in the control of cell growth and cell division. The glypican encoded by this gene is a putative cell surface coreceptor for growth factors, extracellular matrix proteins, proteases and anti-proteases. Mutations in this gene are associated with omodysplasia 1. [provided by RefSeq, Nov 2016]

GPC6-AS2 (HGNC:39910): (GPC6 antisense RNA 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC6	NM_005708.5	c.421G>C	p.Asp141His	missense_variant	Exon 3 of 9	ENST00000377047.9	NP_005699.1
GPC6	XM_017020300.2	c.211G>C	p.Asp71His	missense_variant	Exon 3 of 9		XP_016875789.1
GPC6	XM_047429990.1	c.211G>C	p.Asp71His	missense_variant	Exon 3 of 9		XP_047285946.1
GPC6-AS2	NR_046536.1	n.380+561C>G		intron_variant	Intron 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC6	ENST00000377047.9	c.421G>C	p.Asp141His	missense_variant	Exon 3 of 9	1	NM_005708.5	ENSP00000366246.3
GPC6-AS2	ENST00000445540.1	n.228+561C>G		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 141 of the GPC6 protein (p.Asp141His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GPC6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1946993). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GPC6 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.70		Loss of stability (P = 0.1817);
MVP		0.90
MPC		1.0
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.69
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-94482508;