18-62045884-C-G

Position:

chr18-62045884-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_176787.5(PIGN):c.2768G>C(p.Cys923Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,613,678 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.0530

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040290534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGN	NM_176787.5 linkuse as main transcript	c.2768G>C	p.Cys923Ser	missense_variant	31/31	ENST00000640252.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGN	ENST00000640252.2 linkuse as main transcript	c.2768G>C	p.Cys923Ser	missense_variant	31/31	1	NM_176787.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000482

AC:

AN:

249140

Hom.:

AF XY:

0.0000740

AC XY:

AN XY:

135160

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000797

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000725

AC:

106

AN:

1461544

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000908

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 04, 2022

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 923 of the PIGN protein (p.Cys923Ser). This variant is present in population databases (rs369297861, gnomAD 0.008%). 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: 859862). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jun 01, 2023

BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.60

CADD

Benign

1.2

DANN

Benign

0.62

DEOGEN2

Benign

0.0092

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.80

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

M_CAP

Benign

0.0031

MetaRNN

Benign

0.040

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

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.26

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

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

1.4

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

REVEL

Benign

0.058

Sift

Benign

0.54

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

Sift4G

Benign

0.44

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

Polyphen

0.0

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

Vest4

0.062, 0.075

MutPred

0.35

Gain of disorder (P = 1e-04);.;Gain of disorder (P = 1e-04);Gain of disorder (P = 1e-04);Gain of disorder (P = 1e-04);.;.;.;.;.;Gain of disorder (P = 1e-04);.;.;Gain of disorder (P = 1e-04);.;Gain of disorder (P = 1e-04);

MVP

0.17

MPC

0.026

ClinPred

0.032

GERP RS

0.063

Varity_R

0.049

gMVP

0.17

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over