chr18-62114567-A-C

Variant names:

• chr18-62114567-A-C
• rs13381627
• NM_176787.5:c.1245T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_176787.5(PIGN):​c.1245T>G​(p.Asp415Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Synonymous variant affecting the same amino acid position (i.e. D415D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.567
• Publications: 16 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04461059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5	c.1245T>G	p.Asp415Glu	missense_variant	Exon 15 of 31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.1245T>G	p.Asp415Glu	missense_variant	Exon 15 of 31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.1245T>G	p.Asp415Glu	missense_variant	Exon 14 of 30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.1245T>G		non_coding_transcript_exon_variant	Exon 13 of 29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.026
DANN	Benign	0.31
DEOGEN2	Benign	0.010	T;.;T;T;T;.;.;.;.;T;.;.;T;.;T;.;.;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.65	.;.;.;.;.;.;.;T;T;.;T;T;.;T;T;T;T;.;.;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.045	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.47	N;.;N;N;N;.;.;.;.;N;.;.;N;.;N;.;.;.;.;.
PhyloP100		-0.57
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.11	.;.;.;N;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.028
Sift	Benign	0.51	.;.;.;T;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.90	.;.;.;T;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0010	B;.;B;B;B;.;.;.;.;B;.;.;B;.;B;.;.;.;.;.
Vest4		0.054, 0.053
MutPred		0.26		Loss of MoRF binding (P = 0.0791);.;Loss of MoRF binding (P = 0.0791);Loss of MoRF binding (P = 0.0791);Loss of MoRF binding (P = 0.0791);.;Loss of MoRF binding (P = 0.0791);.;.;Loss of MoRF binding (P = 0.0791);Loss of MoRF binding (P = 0.0791);.;Loss of MoRF binding (P = 0.0791);Loss of MoRF binding (P = 0.0791);Loss of MoRF binding (P = 0.0791);Loss of MoRF binding (P = 0.0791);Loss of MoRF binding (P = 0.0791);Loss of MoRF binding (P = 0.0791);Loss of MoRF binding (P = 0.0791);Loss of MoRF binding (P = 0.0791);
MVP		0.31
MPC		0.023
ClinPred		0.023	T
GERP RS		-2.8
Varity_R		0.036
gMVP		0.075
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs13381627; hg19: chr18-59781800;