rs200658159

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM5BP4_StrongBP6_Very_StrongBS2

The NM_176787.5(PIGN):c.2238A>G(p.Ile746Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,611,218 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I746R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 5 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.108

Publications

7 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 -14 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-62090522-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 659307.

BP4

Computational evidence support a benign effect (MetaRNN=0.006445229).

BP6

Variant 18-62090521-T-C is Benign according to our data. Variant chr18-62090521-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 539565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5 link	c.2238A>G	p.Ile746Met	missense_variant	Exon 24 of 31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PIGN	ENST00000640252.2 link	c.2238A>G	p.Ile746Met	missense_variant	Exon 24 of 31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7 link	c.2238A>G	p.Ile746Met	missense_variant	Exon 23 of 30	1		ENSP00000383188.2
PIGN	ENST00000638424.1 link	n.2238A>G		non_coding_transcript_exon_variant	Exon 22 of 29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes

AF:

0.00113

AC:

172

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00135

AC:

333

AN:

247046

AF XY:

0.00144

show subpopulations

Gnomad AFR exome

AF:

0.000195

Gnomad AMR exome

AF:

0.000294

Gnomad ASJ exome

AF:

0.0179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00117

Gnomad OTH exome

AF:

0.00167

GnomAD4 exome

AF:

0.00120

AC:

1754

AN:

1458906

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

901

AN XY:

725768

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33388

American (AMR)

AF:

0.000360

AC:

AN:

44480

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

450

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39430

South Asian (SAS)

AF:

0.00

AC:

AN:

85740

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00106

AC:

1179

AN:

1110446

Other (OTH)

AF:

0.00171

AC:

103

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

150

226

301

376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.00113

AC:

172

AN:

152312

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41576

American (AMR)

AF:

0.000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00129

AC:

AN:

68016

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.00187

Hom.:

Bravo

AF:

0.00131

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000827

AC:

ESP6500EA

AF:

0.00282

AC:

ExAC

AF:

0.00123

AC:

149

EpiCase

AF:

0.00192

EpiControl

AF:

0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 24, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PIGN: PM5, BP4, BS1, BS2 -

Jul 26, 2018

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jul 27, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.013

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

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.81

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

M_CAP

Benign

0.0084

MetaRNN

Benign

0.0064

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.76

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

PhyloP100

0.11

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.18

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

REVEL

Benign

0.10

Sift

Benign

0.33

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

Sift4G

Benign

0.42

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

Polyphen

0.0020

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

Vest4

0.23

MVP

0.51

MPC

0.024

ClinPred

0.0041

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.047

gMVP

0.22

Mutation Taster

=81/19

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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