rs2298784

Variant names:

• chr18-62109920-T-C
• rs2298784
• NM_176787.5:c.1488A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_176787.5(PIGN):​c.1488A>G​(p.Ala496Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0061 in 1,613,146 control chromosomes in the GnomAD database, including 283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A496A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0097 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (238 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0200
• Publications: 4 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• Fryns syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 18-62109920-T-C is Benign according to our data. Variant chr18-62109920-T-C is described in ClinVar as Benign. ClinVar VariationId is 472211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0629 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176787.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	NM_176787.5	MANE Select	c.1488A>G	p.Ala496Ala	synonymous	Exon 17 of 31	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.1488A>G	p.Ala496Ala	synonymous	Exon 17 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.1488A>G	p.Ala496Ala	synonymous	Exon 16 of 30	NP_036459.1	O95427

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	ENST00000640252.2	TSL:1 MANE Select	c.1488A>G	p.Ala496Ala	synonymous	Exon 17 of 31	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.1488A>G	p.Ala496Ala	synonymous	Exon 16 of 30	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.1488A>G		non_coding_transcript_exon	Exon 15 of 29	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes AF: 0.00967 AC: 1470 AN: 151972 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.00288

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0689

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.0694

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.0125 AC: 3110 AN: 248676 AF XY: 0.0124

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00378

Gnomad EAS exome AF: 0.0628

Gnomad FIN exome AF: 0.0654

Gnomad NFE exome AF: 0.00289

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.00573 AC: 8369 AN: 1461056 Hom.: 238 Cov.: 30 AF XY: 0.00563 AC XY: 4094 AN XY: 726808

African (AFR) AF: 0.00221 AC: 74 AN: 33448

American (AMR) AF: 0.000627 AC: 28 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00429 AC: 112 AN: 26122

East Asian (EAS) AF: 0.0719 AC: 2849 AN: 39606

South Asian (SAS) AF: 0.00274 AC: 236 AN: 86236

European-Finnish (FIN) AF: 0.0629 AC: 3357 AN: 53384

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5760

European-Non Finnish (NFE) AF: 0.00113 AC: 1260 AN: 1111470

Other (OTH) AF: 0.00738 AC: 445 AN: 60338

GnomAD4 genome AF: 0.00966 AC: 1469 AN: 152090 Hom.: 45 Cov.: 32 AF XY: 0.0131 AC XY: 971 AN XY: 74354

African (AFR) AF: 0.00287 AC: 119 AN: 41506

American (AMR) AF: 0.000786 AC: 12 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.0688 AC: 356 AN: 5172

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4824

European-Finnish (FIN) AF: 0.0694 AC: 734 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00281 AC: 191 AN: 67962

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00235 Hom.: 5

Bravo AF: 0.00435

Asia WGS AF: 0.0330 AC: 114 AN: 3478

EpiCase AF: 0.000982

EpiControl AF: 0.000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Multiple congenital anomalies-hypotonia-seizures syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.1
DANN	Benign	0.75
PhyloP100		-0.020
Mutation Taster		=100/0	polymorphism (auto)

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: rs2298784; hg19: chr18-59777153; COSMIC: COSV62949472; COSMIC: COSV62949472;