chr18-62154538-CACAAACCT-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_176787.5(PIGN):c.548_549+6delAGGTTTGT(p.Lys183fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000325 in 1,345,956 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

PIGN
NM_176787.5 frameshift, splice_donor, splice_region, intron

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 8.36

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: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 18-62154538-CACAAACCT-C is Pathogenic according to our data. Variant chr18-62154538-CACAAACCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 264637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5 link	c.548_549+6delAGGTTTGT	p.Lys183fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_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.548_549+6delAGGTTTGT	p.Lys183fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 7 of 31	1	NM_176787.5	ENSP00000492233.1	O95427
PIGN	ENST00000400334.7 link	c.548_549+6delAGGTTTGT	p.Lys183fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 6 of 30	1		ENSP00000383188.2	O95427
PIGN	ENST00000638424.1 link	n.548_549+6delAGGTTTGT		splice_donor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	Exon 5 of 29	5		ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

151714

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000130

AC:

AN:

245596

AF XY:

0.000143

show subpopulations

Gnomad AFR exome

AF:

0.0000649

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:

0.000259

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000353

AC:

421

AN:

1194242

Hom.:

AF XY:

0.000318

AC XY:

193

AN XY:

607212

show subpopulations

African (AFR)

AF:

0.0000709

AC:

AN:

28220

American (AMR)

AF:

0.00

AC:

AN:

43682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24402

East Asian (EAS)

AF:

0.00

AC:

AN:

38358

South Asian (SAS)

AF:

0.00

AC:

AN:

79402

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5274

European-Non Finnish (NFE)

AF:

0.000463

AC:

403

AN:

870736

Other (OTH)

AF:

0.000311

AC:

AN:

51404

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000105

AC:

AN:

151714

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74124

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41052

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000136

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1

Pathogenic:4

Sep 28, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 25, 2024

Johns Hopkins Genomics, Johns Hopkins University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This PIGN variant (rs779636222) is rare (<0.1%) in a large population dataset (gnomAD: 36/276898 total alleles; 0.013%; no homozygotes) and has an entry in ClinVar. It has been reported in one individual with multiple congenital anomalies-hypotonia-seizures syndrome in a compound heterozygous state with another pathogenic variant. This 8-bp deletion (ACAAACCT) covers two coding nucleotides and six intronic nucleotides, including the canonical splice donor site and is predicted to cause aberrant pre-mRNA splicing. We consider c.548_549+6del to be pathogenic for autosomal recessive multiple congenital anomalies-hypotonia-seizures syndrome-1. -

Jun 23, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant results in the deletion of part of exon 7 (c.548_549+6del) of the PIGN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PIGN are known to be pathogenic (PMID: 24253414, 27038415). This variant is present in population databases (rs779636222, gnomAD 0.03%). This variant has been observed in individual(s) with clinical features of multiple congenital anomalies-hypotonia-seizures syndrome (PMID: 26394714, 30293990, 30609409). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 264637). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Apr 26, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 26, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27038415, 24253414, 26394714, 30609409, 30293990) -

Inborn genetic diseases

Pathogenic:1

Jan 03, 2018

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.548_549+6delAGGTTTGT pathogenic mutation, located at the 3' end of coding exon 4 in the PIGN gene, results from a deletion of 2 coding nucleotides and 6 intronic nucleotides at positions c.548 to c.549+6, including the canonical donor site. In one study, this mutation was detected in an individual with multiple congenital anomalies-hypotonia-seizures syndrome who also carried a second PIGN alteration in trans (a gross deletion encompassing multiple exons) (Fleming, L. 2016. Am. J. Med. Genet. A 2016 Jan;170A(1):77-86). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Multiple congenital anomalies-hypotonia-seizures syndrome

Pathogenic:1

May 10, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.548_549+6delAGGTTTGT variant in PIGN has been reported in one patient with multiple congenital anomalies-hypotonia-seizures syndrome in a compound heteroz ygous state (Fleming 2016) and has been identified in 13/120594 chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enou gh to be consistent with a recessive carrier frequency. This deletion encompasse s the invariant region (+/- 1,2) of the splice consensus sequence and is predict ed to cause altered splicing leading to an abnormal or absent protein. Biallelic loss of function of the PIGN gene has been associated with multiple congenital anomalies-hypotonia-seizures syndrome. In summary, although additional studies a re required to fully establish its clinical significance, the c.548_549+6del var iant in PIGN is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.4

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

Splicing

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

Publications

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chr18-62154538-CACAAACCT-C

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