18-62045869-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_176787.5(PIGN):c.2783G>A(p.Ser928Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,613,826 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.952

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

multiple congenital anomalies-hypotonia-seizures syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet, ClinGen, PanelApp Australia
Fryns syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PIGN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056847334).

BP6

Variant 18-62045869-C-T is Benign according to our data. Variant chr18-62045869-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 472229.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5 link	c.2783G>A	p.Ser928Asn	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.2783G>A	p.Ser928Asn	missense_variant	Exon 31 of 31	1	NM_176787.5	ENSP00000492233.1	O95427
PIGN	ENST00000400334.7 link	c.2783G>A	p.Ser928Asn	missense_variant	Exon 30 of 30	1		ENSP00000383188.2	O95427
PIGN	ENST00000638424.1 link	n.*751G>A		non_coding_transcript_exon_variant	Exon 29 of 29	5		ENSP00000491963.1	A0A1W2PQZ1
PIGN	ENST00000638424.1 link	n.*751G>A		3_prime_UTR_variant	Exon 29 of 29	5		ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

161

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00612

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000871

AC:

217

AN:

249112

AF XY:

0.000821

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00539

Gnomad NFE exome

AF:

0.000797

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.00111

AC:

1628

AN:

1461494

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

783

AN XY:

727034

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33470

American (AMR)

AF:

0.0000447

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00727

AC:

388

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00106

AC:

1182

AN:

1111736

Other (OTH)

AF:

0.000861

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

152

229

305

381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00106

AC:

161

AN:

152332

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41578

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00612

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00129

AC:

AN:

68042

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000829

Hom.:

Bravo

AF:

0.000472

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000253

AC:

ESP6500EA

AF:

0.00108

AC:

ExAC

AF:

0.000926

AC:

112

EpiCase

AF:

0.000709

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 26, 2016

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S928N variant (also known as c.2783G>A), located in coding exon 28 of the PIGN gene, results from a G to A substitution at nucleotide position 2783. The serine at codon 928 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PIGN-related disorder

Benign:1

Sep 12, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.0090

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

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.84

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

M_CAP

Benign

0.0077

MetaRNN

Benign

0.0057

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.;L;L;L;.;.;.;.;.;L;.;.;L;.;L

PhyloP100

0.95

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.12

.;.;.;N;.;.;.;.;.;.;N;.;.;.;.;.

REVEL

Benign

0.021

Sift

Benign

0.47

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

Sift4G

Benign

0.51

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

Polyphen

0.0010

B;.;B;B;B;.;.;.;.;.;B;.;.;B;.;B

Vest4

0.093, 0.090

MVP

0.48

MPC

0.027

ClinPred

0.017

GERP RS

4.3

Varity_R

0.056

gMVP

0.10

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over