18-62045876-G-T

Position:

• chr18-62045876-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_176787.5(PIGN):​c.2776C>A​(p.Pro926Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0620

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057001054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGN	NM_176787.5	c.2776C>A	p.Pro926Thr	missense_variant	31/31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.2776C>A	p.Pro926Thr	missense_variant	31/31	1	NM_176787.5	ENSP00000492233	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461488 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 10, 2022

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 926 of the PIGN protein (p.Pro926Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PIGN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.3
DANN	Benign	0.73
DEOGEN2	Benign	0.011	T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.79	.;.;.;.;.;.;T;.;T;T;.;T;T;.;T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.057	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.85	L;.;L;L;L;.;.;.;.;.;L;.;.;L;.;L
MutationTaster	Benign	0.81	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.18	.;.;.;N;.;.;.;.;.;.;N;.;.;.;.;.
REVEL	Benign	0.036
Sift	Benign	0.19	.;.;.;T;.;.;.;.;.;.;T;.;.;.;.;.
Sift4G	Benign	0.31	.;.;.;T;.;.;.;.;.;.;T;.;.;.;.;.
Polyphen		0.0	B;.;B;B;B;.;.;.;.;.;B;.;.;B;.;B
Vest4		0.034, 0.035
MutPred		0.27		Gain of MoRF binding (P = 0.0234);.;Gain of MoRF binding (P = 0.0234);Gain of MoRF binding (P = 0.0234);Gain of MoRF binding (P = 0.0234);.;.;.;.;.;Gain of MoRF binding (P = 0.0234);.;.;Gain of MoRF binding (P = 0.0234);.;Gain of MoRF binding (P = 0.0234);
MVP		0.34
MPC		0.025
ClinPred		0.15	T
GERP RS		-0.65
Varity_R		0.039
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1599384266; hg19: chr18-59713109;