rs17069506

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.484A>G(p.Lys162Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0438 in 1,587,798 control chromosomes in the GnomAD database, including 2,017 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. K162T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.052 ( 251 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1766 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0490

Publications

15 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=0.0016021132).

BP6

Variant 18-62154610-T-C is Benign according to our data. Variant chr18-62154610-T-C is described in ClinVar as Benign. ClinVar VariationId is 403309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5 link	c.484A>G	p.Lys162Glu	missense_variant	Exon 7 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.484A>G	p.Lys162Glu	missense_variant	Exon 7 of 31	1	NM_176787.5	ENSP00000492233.1	O95427
PIGN	ENST00000400334.7 link	c.484A>G	p.Lys162Glu	missense_variant	Exon 6 of 30	1		ENSP00000383188.2	O95427
PIGN	ENST00000638424.1 link	n.484A>G		non_coding_transcript_exon_variant	Exon 5 of 29	5		ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes

AF:

0.0516

AC:

7849

AN:

152054

Hom.:

251

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0741

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0424

Gnomad ASJ

AF:

0.0844

Gnomad EAS

AF:

0.0767

Gnomad SAS

AF:

0.0839

Gnomad FIN

AF:

0.0340

Gnomad MID

AF:

0.137

Gnomad NFE

AF:

0.0369

Gnomad OTH

AF:

0.0612

GnomAD2 exomes

AF:

0.0518

AC:

12836

AN:

247846

AF XY:

0.0537

show subpopulations

Gnomad AFR exome

AF:

0.0783

Gnomad AMR exome

AF:

0.0310

Gnomad ASJ exome

AF:

0.0864

Gnomad EAS exome

AF:

0.0797

Gnomad FIN exome

AF:

0.0347

Gnomad NFE exome

AF:

0.0398

Gnomad OTH exome

AF:

0.0584

GnomAD4 exome

AF:

0.0429

AC:

61639

AN:

1435626

Hom.:

1766

Cov.:

AF XY:

0.0448

AC XY:

32040

AN XY:

715826

show subpopulations

African (AFR)

AF:

0.0792

AC:

2596

AN:

32768

American (AMR)

AF:

0.0321

AC:

1430

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.0866

AC:

2247

AN:

25946

East Asian (EAS)

AF:

0.0753

AC:

2971

AN:

39440

South Asian (SAS)

AF:

0.0884

AC:

7539

AN:

85268

European-Finnish (FIN)

AF:

0.0339

AC:

1789

AN:

52776

Middle Eastern (MID)

AF:

0.144

AC:

822

AN:

5718

European-Non Finnish (NFE)

AF:

0.0359

AC:

39143

AN:

1089692

Other (OTH)

AF:

0.0522

AC:

3102

AN:

59452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

2524

5048

7571

10095

12619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1562

3124

4686

6248

7810

<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:

0.0517

AC:

7866

AN:

152172

Hom.:

251

Cov.:

AF XY:

0.0526

AC XY:

3916

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0742

AC:

3079

AN:

41494

American (AMR)

AF:

0.0423

AC:

647

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0844

AC:

293

AN:

3470

East Asian (EAS)

AF:

0.0770

AC:

400

AN:

5192

South Asian (SAS)

AF:

0.0841

AC:

405

AN:

4814

European-Finnish (FIN)

AF:

0.0340

AC:

361

AN:

10616

Middle Eastern (MID)

AF:

0.140

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0369

AC:

2508

AN:

67974

Other (OTH)

AF:

0.0624

AC:

132

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

374

748

1123

1497

1871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<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:

0.0430

Hom.:

509

Bravo

AF:

0.0526

TwinsUK

AF:

0.0361

AC:

134

ALSPAC

AF:

0.0384

AC:

148

ESP6500AA

AF:

0.0745

AC:

273

ESP6500EA

AF:

0.0405

AC:

331

ExAC

AF:

0.0538

AC:

6503

Asia WGS

AF:

0.0710

AC:

246

AN:

3476

EpiCase

AF:

0.0451

EpiControl

AF:

0.0456

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

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: MAF -

Inborn genetic diseases

Benign:1

Apr 07, 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. -

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Benign:1

Feb 03, 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

0.052

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.11

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.012

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

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.64

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

MetaRNN

Benign

0.0016

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;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-3.3

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

PhyloP100

0.049

PrimateAI

Benign

0.21

PROVEAN

Benign

3.0

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

REVEL

Benign

0.13

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0

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

Vest4

0.017

MPC

0.027

ClinPred

0.0042

GERP RS

-2.9

PromoterAI

0.039

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.050

gMVP

0.23

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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