rs368921294

Variant names:

• chr18-62084585-A-G
• rs368921294
• NM_176787.5:c.2448T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_176787.5(PIGN):​c.2448T>C​(p.Tyr816Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,557,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.17
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 18-62084585-A-G is Benign according to our data. Variant chr18-62084585-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 472220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.17 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5	c.2448T>C	p.Tyr816Tyr	synonymous_variant	Exon 27 of 31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.2448T>C	p.Tyr816Tyr	synonymous_variant	Exon 27 of 31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.2448T>C	p.Tyr816Tyr	synonymous_variant	Exon 26 of 30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.*416T>C		non_coding_transcript_exon_variant	Exon 25 of 29	5		ENSP00000491963.1
PIGN	ENST00000638424.1	n.*416T>C		3_prime_UTR_variant	Exon 25 of 29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000985 AC: 17 AN: 172532 AF XY: 0.000121

Gnomad AFR exome AF: 0.000210

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000229

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000170

Gnomad OTH exome AF: 0.000213

GnomAD4 exome AF: 0.000162 AC: 227 AN: 1405538 Hom.: 0 Cov.: 28 AF XY: 0.000167 AC XY: 116 AN XY: 694276

African (AFR) AF: 0.0000942 AC: 3 AN: 31840

American (AMR) AF: 0.00 AC: 0 AN: 37024

Ashkenazi Jewish (ASJ) AF: 0.000317 AC: 8 AN: 25226

East Asian (EAS) AF: 0.00 AC: 0 AN: 36630

South Asian (SAS) AF: 0.00 AC: 0 AN: 79528

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.000191 AC: 207 AN: 1080944

Other (OTH) AF: 0.000137 AC: 8 AN: 58392

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74366

African (AFR) AF: 0.000193 AC: 8 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PIGN: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.9
DANN	Benign	0.41
PhyloP100		1.2

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

Other links and lift over

dbSNP: rs368921294; hg19: chr18-59751818;