dbSNP rs200756305: PIGN:p.Glu122Gln (chr18-62157207-C-G) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_176787.5(PIGN):c.364G>C(p.Glu122Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000602 in 1,605,066 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E122A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00061 ( 4 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 7.75

Publications

2 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11295295).

BP6

Variant 18-62157207-C-G is Benign according to our data. Variant chr18-62157207-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218858.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000611 (888/1452802) while in subpopulation MID AF = 0.0101 (58/5744). AF 95% confidence interval is 0.00802. There are 4 homozygotes in GnomAdExome4. There are 526 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176787.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIGN	NM_176787.5	MANE Select	c.364G>C	p.Glu122Gln	missense	Exon 6 of 31	NP_789744.1
PIGN	NM_001438896.1		c.364G>C	p.Glu122Gln	missense	Exon 6 of 32	NP_001425825.1
PIGN	NM_012327.6		c.364G>C	p.Glu122Gln	missense	Exon 5 of 30	NP_036459.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIGN	ENST00000640252.2	TSL:1 MANE Select	c.364G>C	p.Glu122Gln	missense	Exon 6 of 31	ENSP00000492233.1
PIGN	ENST00000400334.7	TSL:1	c.364G>C	p.Glu122Gln	missense	Exon 5 of 30	ENSP00000383188.2
PIGN	ENST00000638424.1	TSL:5	n.364G>C		non_coding_transcript_exon	Exon 4 of 29	ENSP00000491963.1

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000737

AC:

178

AN:

241568

AF XY:

0.000880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000504

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000567

Gnomad NFE exome

AF:

0.000990

Gnomad OTH exome

AF:

0.00137

GnomAD4 exome

AF:

0.000611

AC:

888

AN:

1452802

Hom.:

Cov.:

AF XY:

0.000728

AC XY:

526

AN XY:

722566

show subpopulations

African (AFR)

AF:

0.000390

AC:

AN:

33364

American (AMR)

AF:

0.000542

AC:

AN:

44280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25964

East Asian (EAS)

AF:

0.00

AC:

AN:

39492

South Asian (SAS)

AF:

0.00102

AC:

AN:

84964

European-Finnish (FIN)

AF:

0.000528

AC:

AN:

53024

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000553

AC:

612

AN:

1105884

Other (OTH)

AF:

0.00110

AC:

AN:

60086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

105

140

175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000512

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41544

American (AMR)

AF:

0.000523

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68018

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.000813

Hom.:

Bravo

AF:

0.000567

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000274

AC:

ESP6500EA

AF:

0.000491

AC:

ExAC

AF:

0.000712

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 29, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PIGN: BS2

not specified

Uncertain:1

May 11, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Uncertain:1

Jun 27, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.364G>C (p.E122Q) alteration is located in exon 6 (coding exon 3) of the PIGN gene. This alteration results from a G to C substitution at nucleotide position 364, causing the glutamic acid (E) at amino acid position 122 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PIGN-related disorder

Benign:1

Jun 24, 2024

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.036

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.024

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.82

MutationAssessor

Pathogenic

3.1

PhyloP100

7.8

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.7

REVEL

Benign

0.19

Sift

Benign

0.045

Sift4G

Uncertain

0.039

Polyphen

0.99

Vest4

0.41

MVP

0.77

MPC

0.17

ClinPred

0.14

GERP RS

5.4

Varity_R

0.26

gMVP

0.70

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over