chr18-62090529-T-C

Variant names:

• chr18-62090529-T-C
• rs374860427
• NM_176787.5:c.2230A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_176787.5(PIGN):​c.2230A>G​(p.Ile744Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,459,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.92
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	NM_176787.5	MANE Select	c.2230A>G	p.Ile744Val	missense	Exon 24 of 31	NP_789744.1
	PIGN	NM_001438896.1		c.2230A>G	p.Ile744Val	missense	Exon 24 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.2230A>G	p.Ile744Val	missense	Exon 23 of 30	NP_036459.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	ENST00000640252.2	TSL:1 MANE Select	c.2230A>G	p.Ile744Val	missense	Exon 24 of 31	ENSP00000492233.1
	PIGN	ENST00000400334.7	TSL:1	c.2230A>G	p.Ile744Val	missense	Exon 23 of 30	ENSP00000383188.2
	PIGN	ENST00000638424.1	TSL:5	n.2230A>G		non_coding_transcript_exon	Exon 22 of 29	ENSP00000491963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247526 AF XY: 0.00000745

Gnomad AFR exome AF: 0.00

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: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1459354 Hom.: 0 Cov.: 28 AF XY: 0.0000110 AC XY: 8 AN XY: 726014

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39442

South Asian (SAS) AF: 0.00 AC: 0 AN: 85928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1110570

Other (OTH) AF: 0.00 AC: 0 AN: 60264

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000245 AC: 2

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1 Uncertain:1

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with valine at codon 744 of the PIGN protein (p.Ile744Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs374860427, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with PIGN-related conditions. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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

Jun 22, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L
PhyloP100		6.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	0.64	T
Polyphen		0.97	D
Vest4		0.64
MVP		0.58
MPC		0.042
ClinPred		0.75	D
GERP RS		5.5
Varity_R		0.099
gMVP		0.15
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: 49

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs374860427; hg19: chr18-59757762;