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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 264637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.548_549+6delAGGTTTGT	p.Lys183fs	frameshift splice_donor splice_region intron	Exon 7 of 31	NP_789744.1
PIGN	NM_001438896.1		c.548_549+6delAGGTTTGT	p.Lys183fs	frameshift splice_donor splice_region intron	Exon 7 of 32	NP_001425825.1
PIGN	NM_012327.6		c.548_549+6delAGGTTTGT	p.Lys183fs	frameshift splice_donor splice_region intron	Exon 6 of 30	NP_036459.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIGN	ENST00000640252.2	TSL:1 MANE Select	c.548_549+6delAGGTTTGT	p.Lys183fs	frameshift splice_donor splice_region intron	Exon 7 of 31	ENSP00000492233.1
PIGN	ENST00000400334.7	TSL:1	c.548_549+6delAGGTTTGT	p.Lys183fs	frameshift splice_donor splice_region intron	Exon 6 of 30	ENSP00000383188.2
PIGN	ENST00000638424.1	TSL:5	n.548_549+6delAGGTTTGT		splice_donor splice_region intron non_coding_transcript_exon	Exon 5 of 29	ENSP00000491963.1

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

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:

0.000105

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

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:

0.000174

Hom.:

Bravo

AF:

0.000136

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Multiple congenital anomalies-hypotonia-seizures syndrome 1 (4)

not provided (2)

Inborn genetic diseases (1)

Multiple congenital anomalies-hypotonia-seizures syndrome (1)

Computational scores

Source: dbNSFP v4.9

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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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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over