18-62147091-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_176787.5(PIGN):c.685C>G(p.His229Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,587,026 control chromosomes in the GnomAD database, including 468,501 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H229R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.80 ( 48759 hom., cov: 32)

Exomes 𝑓: 0.76 ( 419742 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.89

Publications

37 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.619225E-7).

BP6

Variant 18-62147091-G-C is Benign according to our data. Variant chr18-62147091-G-C is described in ClinVar as Benign. ClinVar VariationId is 403308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5 link	c.685C>G	p.His229Asp	missense_variant	Exon 9 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.685C>G	p.His229Asp	missense_variant	Exon 9 of 31	1	NM_176787.5	ENSP00000492233.1	O95427
PIGN	ENST00000400334.7 link	c.685C>G	p.His229Asp	missense_variant	Exon 8 of 30	1		ENSP00000383188.2	O95427
PIGN	ENST00000638424.1 link	n.685C>G		non_coding_transcript_exon_variant	Exon 7 of 29	5		ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes

AF:

0.798

AC:

121287

AN:

152032

Hom.:

48693

Cov.:

show subpopulations

Gnomad AFR

AF:

0.873

Gnomad AMI

AF:

0.706

Gnomad AMR

AF:

0.814

Gnomad ASJ

AF:

0.817

Gnomad EAS

AF:

0.909

Gnomad SAS

AF:

0.851

Gnomad FIN

AF:

0.753

Gnomad MID

AF:

0.835

Gnomad NFE

AF:

0.743

Gnomad OTH

AF:

0.792

GnomAD2 exomes

AF:

0.788

AC:

190899

AN:

242216

AF XY:

0.786

show subpopulations

Gnomad AFR exome

AF:

0.873

Gnomad AMR exome

AF:

0.826

Gnomad ASJ exome

AF:

0.819

Gnomad EAS exome

AF:

0.912

Gnomad FIN exome

AF:

0.745

Gnomad NFE exome

AF:

0.734

Gnomad OTH exome

AF:

0.784

GnomAD4 exome

AF:

0.762

AC:

1093869

AN:

1434876

Hom.:

419742

Cov.:

AF XY:

0.764

AC XY:

545741

AN XY:

714358

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.877

AC:

29071

AN:

33166

American (AMR)

AF:

0.826

AC:

36294

AN:

43952

Ashkenazi Jewish (ASJ)

AF:

0.819

AC:

21129

AN:

25810

East Asian (EAS)

AF:

0.879

AC:

34565

AN:

39330

South Asian (SAS)

AF:

0.845

AC:

72013

AN:

85222

European-Finnish (FIN)

AF:

0.744

AC:

39490

AN:

53056

Middle Eastern (MID)

AF:

0.838

AC:

4786

AN:

5714

European-Non Finnish (NFE)

AF:

0.744

AC:

809995

AN:

1089248

Other (OTH)

AF:

0.784

AC:

46526

AN:

59378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.399

Heterozygous variant carriers

11820

23639

35459

47278

59098

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19818

39636

59454

79272

99090

<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:

0.798

AC:

121409

AN:

152150

Hom.:

48759

Cov.:

AF XY:

0.799

AC XY:

59445

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.873

AC:

36287

AN:

41548

American (AMR)

AF:

0.814

AC:

12445

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.817

AC:

2835

AN:

3472

East Asian (EAS)

AF:

0.908

AC:

4712

AN:

5188

South Asian (SAS)

AF:

0.852

AC:

4109

AN:

4822

European-Finnish (FIN)

AF:

0.753

AC:

7946

AN:

10554

Middle Eastern (MID)

AF:

0.830

AC:

244

AN:

294

European-Non Finnish (NFE)

AF:

0.743

AC:

50515

AN:

67970

Other (OTH)

AF:

0.792

AC:

1672

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1268

2536

3805

5073

6341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

872

1744

2616

3488

4360

<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:

0.763

Hom.:

14479

Bravo

AF:

0.806

TwinsUK

AF:

0.742

AC:

2753

ALSPAC

AF:

0.745

AC:

2870

ESP6500AA

AF:

0.878

AC:

3151

ESP6500EA

AF:

0.753

AC:

6121

ExAC

AF:

0.782

AC:

94288

Asia WGS

AF:

0.864

AC:

2992

AN:

3460

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 11, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.010

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

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.46

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

MetaRNN

Benign

9.6e-7

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.2

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

PhyloP100

1.9

PrimateAI

Benign

0.36

PROVEAN

Benign

0.010

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

REVEL

Benign

0.082

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0

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

Vest4

0.043

MPC

0.027

ClinPred

0.00068

GERP RS

3.7

Varity_R

0.10

gMVP

0.35

Mutation Taster

=98/2

polymorphism (auto)

(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