rs199573774

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_176787.5(PIGN):c.2679C>G(p.Ser893Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000955 in 1,612,328 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 1.96

Variant links:

Genes affected

PIGN (HGNC:8967): (phosphatidylinositol glycan anchor biosynthesis class N) This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This protein is expressed in the endoplasmic reticulum and transfers phosphoethanolamine (EtNP) to the first mannose of the GPI anchor. Two alternatively spliced variants, which encode an identical isoform, have been reported. [provided by RefSeq, Jul 2008]

PIGN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 18-62045973-G-C is Pathogenic according to our data. Variant chr18-62045973-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449082.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5 link	c.2679C>G	p.Ser893Arg	missense_variant	Exon 31 of 31	ENST00000640252.2	NP_789744.1	O95427A0A024R2C3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PIGN	ENST00000640252.2 link	c.2679C>G	p.Ser893Arg	missense_variant	Exon 31 of 31	1	NM_176787.5	ENSP00000492233.1	O95427
PIGN	ENST00000400334.7 link	c.2679C>G	p.Ser893Arg	missense_variant	Exon 30 of 30	1		ENSP00000383188.2	O95427
PIGN	ENST00000638424.1 link	n.*647C>G		non_coding_transcript_exon_variant	Exon 29 of 29	5		ENSP00000491963.1	A0A1W2PQZ1
PIGN	ENST00000638424.1 link	n.*647C>G		3_prime_UTR_variant	Exon 29 of 29	5		ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000134

AC:

AN:

246180

Hom.:

AF XY:

0.000157

AC XY:

AN XY:

133356

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000586

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000433

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.000143

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000897

AC:

131

AN:

1460002

Hom.:

Cov.:

AF XY:

0.0000937

AC XY:

AN XY:

726052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000674

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000385

Gnomad4 FIN exome

AF:

0.0000750

Gnomad4 NFE exome

AF:

0.0000765

Gnomad4 OTH exome

AF:

0.0000995

GnomAD4 genome

AF:

0.000151

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000256

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.000174

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Pathogenic:2Uncertain:1

Apr 23, 2019

Centogene AG - the Rare Disease Company

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as compound heterozygous. -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 893 of the PIGN protein (p.Ser893Arg). This variant is present in population databases (rs199573774, gnomAD 0.04%). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy and/or PIGN-related disease (PMID: 35179230, 36322149; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 449082). 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 expected to disrupt PIGN protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1Uncertain:1

May 02, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect, specifically p.(S893R) showed complete impairment of PIGN activity (PMID: 36322149); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26633542, 34426522, 35179230, 36672771, 36322149, 27119594) -

Sep 16, 2022

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.97

.;.;.;.;.;.;D;.;D;D;.;D;D;.;D;D

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.48

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Pathogenic

3.4

M;.;M;M;M;.;.;.;.;.;M;.;.;M;.;M

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-4.3

.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.

Sift4G

Uncertain

0.0020

.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.

Polyphen

0.99

D;.;D;D;D;.;.;.;.;.;D;.;.;D;.;D

Vest4

0.89, 0.90

MutPred

0.63

Loss of glycosylation at S891 (P = 0.1612);.;Loss of glycosylation at S891 (P = 0.1612);Loss of glycosylation at S891 (P = 0.1612);Loss of glycosylation at S891 (P = 0.1612);.;.;.;.;.;Loss of glycosylation at S891 (P = 0.1612);.;.;Loss of glycosylation at S891 (P = 0.1612);.;Loss of glycosylation at S891 (P = 0.1612);

MVP

0.70

MPC

0.20

ClinPred

0.89

GERP RS

3.4

Varity_R

0.80

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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