rs200750917

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_176787.5(PIGN):c.2447A>G(p.Tyr816Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000264 in 1,556,908 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y816S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.81

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5 link	c.2447A>G	p.Tyr816Cys	missense_variant	Exon 27 of 31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PIGN	ENST00000640252.2 link	c.2447A>G	p.Tyr816Cys	missense_variant	Exon 27 of 31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7 link	c.2447A>G	p.Tyr816Cys	missense_variant	Exon 26 of 30	1		ENSP00000383188.2
PIGN	ENST00000638424.1 link	n.*415A>G		non_coding_transcript_exon_variant	Exon 25 of 29	5		ENSP00000491963.1
PIGN	ENST00000638424.1 link	n.*415A>G		3_prime_UTR_variant	Exon 25 of 29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000581

AC:

AN:

172252

AF XY:

0.0000772

show subpopulations

Gnomad AFR exome

AF:

0.000105

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000213

GnomAD4 exome

AF:

0.000280

AC:

394

AN:

1404870

Hom.:

Cov.:

AF XY:

0.000280

AC XY:

194

AN XY:

693988

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31838

American (AMR)

AF:

0.00

AC:

AN:

36988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25218

East Asian (EAS)

AF:

0.00

AC:

AN:

36600

South Asian (SAS)

AF:

0.0000252

AC:

AN:

79500

European-Finnish (FIN)

AF:

0.0000199

AC:

AN:

50242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.000352

AC:

380

AN:

1080418

Other (OTH)

AF:

0.000188

AC:

AN:

58372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000112

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41408

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.549

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:

0.000175

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000613

AC:

ExAC

AF:

0.0000872

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Mar 27, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Sep 28, 2018

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jun 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2447A>G (p.Y816C) alteration is located in exon 27 (coding exon 24) of the PIGN gene. This alteration results from a A to G substitution at nucleotide position 2447, causing the tyrosine (Y) at amino acid position 816 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Uncertain:1

Aug 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 816 of the PIGN protein (p.Tyr816Cys). This variant is present in population databases (rs200750917, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PIGN-related conditions. ClinVar contains an entry for this variant (Variation ID: 643029). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PIGN protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

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

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

.;.;.;.;.;.;D;.;D;D;.;D;D;.;D;D;D;D

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.73

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.3

M;.;M;M;M;.;.;.;.;.;M;.;.;M;.;M;.;.

PhyloP100

6.8

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.1

.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.

REVEL

Uncertain

0.48

Sift

Benign

0.16

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

Sift4G

Benign

0.096

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

Polyphen

1.0

D;.;D;D;D;.;.;.;.;.;D;.;.;D;.;D;.;.

Vest4

0.99

MVP

0.88

MPC

0.21

ClinPred

0.95

GERP RS

4.4

Varity_R

0.35

gMVP

0.70

Mutation Taster

=68/32

polymorphism

(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