rs369249247

Variant names:

• chr18-62095936-C-A
• rs369249247
• NM_176787.5:c.2092G>T

Your query was ambiguous. Multiple possible variants found:

• chr18-62095936-C-A
• chr18-62095936-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_176787.5(PIGN):​c.2092G>T​(p.Val698Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V698M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.117343366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5	c.2092G>T	p.Val698Leu	missense_variant	Exon 23 of 31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.2092G>T	p.Val698Leu	missense_variant	Exon 23 of 31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.2092G>T	p.Val698Leu	missense_variant	Exon 22 of 30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.2092G>T		non_coding_transcript_exon_variant	Exon 21 of 29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457626 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 725328

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 86044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108452

Other (OTH) AF: 0.00 AC: 0 AN: 60236

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.1
DANN	Benign	0.18
DEOGEN2	Benign	0.0096	T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T;.;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.87	.;.;.;.;.;.;D;.;D;D;.;D;D;.;D;D;D;D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.040	N;.;N;N;N;.;.;.;.;.;N;.;.;N;.;N;.;.
PhyloP100		1.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.58	.;.;.;N;.;.;.;.;.;.;N;.;.;.;.;.;.;.
REVEL	Benign	0.082
Sift	Benign	1.0	.;.;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.;.
Sift4G	Benign	1.0	.;.;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.;.
Polyphen		0.0010	B;.;B;B;B;.;.;.;.;.;B;.;.;B;.;B;.;.
Vest4		0.11, 0.11
MutPred		0.57		Gain of glycosylation at P699 (P = 0.0654);.;Gain of glycosylation at P699 (P = 0.0654);Gain of glycosylation at P699 (P = 0.0654);Gain of glycosylation at P699 (P = 0.0654);.;.;Gain of glycosylation at P699 (P = 0.0654);.;.;Gain of glycosylation at P699 (P = 0.0654);Gain of glycosylation at P699 (P = 0.0654);.;Gain of glycosylation at P699 (P = 0.0654);.;Gain of glycosylation at P699 (P = 0.0654);Gain of glycosylation at P699 (P = 0.0654);Gain of glycosylation at P699 (P = 0.0654);
MVP		0.43
MPC		0.024
ClinPred		0.024	T
GERP RS		1.1
Varity_R		0.029
gMVP		0.15
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs369249247; hg19: chr18-59763169;