NM_176787.5:c.2126G>T

Variant names:

• chr18-62095902-C-A
• rs397514475
• NM_176787.5:c.2126G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_176787.5(PIGN):​c.2126G>T​(p.Arg709Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. R709Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.83
• 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Fryns syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-62095902-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	NM_176787.5	MANE Select	c.2126G>T	p.Arg709Leu	missense	Exon 23 of 31	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.2126G>T	p.Arg709Leu	missense	Exon 23 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.2126G>T	p.Arg709Leu	missense	Exon 22 of 30	NP_036459.1	O95427

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	ENST00000640252.2	TSL:1 MANE Select	c.2126G>T	p.Arg709Leu	missense	Exon 23 of 31	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.2126G>T	p.Arg709Leu	missense	Exon 22 of 30	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.2126G>T		non_coding_transcript_exon	Exon 21 of 29	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Multiple congenital anomalies-hypotonia-seizures syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.86		Gain of helix (P = 0.0496)
MVP		0.91
MPC		0.21
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.81
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.30		Position offset: 48

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

Other links and lift over

dbSNP: rs397514475; hg19: chr18-59763135;