rs12326381

Positions:

• chr18-62102800-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_176787.5(PIGN):​c.1962G>A​(p.Leu654Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,456,732 control chromosomes in the GnomAD database, including 36,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2947 hom., cov: 31)
  • Exomes 𝑓: 0.22 (33565 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.52

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 18-62102800-C-T is Benign according to our data. Variant chr18-62102800-C-T is described in ClinVar as [Benign]. Clinvar id is 403301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGN	NM_176787.5	c.1962G>A	p.Leu654Leu	synonymous_variant	21/31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.1962G>A	p.Leu654Leu	synonymous_variant	21/31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.1962G>A	p.Leu654Leu	synonymous_variant	20/30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.1962G>A		non_coding_transcript_exon_variant	19/29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25968 AN: 152014 Hom.: 2946 Cov.: 31

Gnomad AFR AF: 0.0499

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.166 AC: 29527 AN: 177866 Hom.: 3113 AF XY: 0.166 AC XY: 15716 AN XY: 94490

Gnomad AFR exome AF: 0.0406

Gnomad AMR exome AF: 0.0996

Gnomad ASJ exome AF: 0.248

Gnomad EAS exome AF: 0.00272

Gnomad SAS exome AF: 0.103

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.217 AC: 283249 AN: 1304598 Hom.: 33565 Cov.: 18 AF XY: 0.216 AC XY: 140140 AN XY: 649912

Gnomad4 AFR exome AF: 0.0401

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.00140

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.242

Gnomad4 OTH exome AF: 0.202

GnomAD4 genome AF: 0.171 AC: 25975 AN: 152134 Hom.: 2947 Cov.: 31 AF XY: 0.168 AC XY: 12491 AN XY: 74374

Gnomad4 AFR AF: 0.0497

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.251

Gnomad4 EAS AF: 0.00521

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.194

Alfa AF: 0.237 Hom.: 6611

Bravo AF: 0.159

Asia WGS AF: 0.0800 AC: 280 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.36
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs12326381; hg19: chr18-59770033; COSMIC: COSV62952137; COSMIC: COSV62952137;