18-62074825-GA-GAA

Variant names:

• chr18-62074825-G-GA
• rs138671843
• NM_176787.5:c.2577-5dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_176787.5(PIGN):​c.2577-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 1,565,040 control chromosomes in the GnomAD database, including 215 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (174 hom.)
• Consequence: PIGN NM_176787.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0730
• Publications: 2 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, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Fryns syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 18-62074825-G-GA is Benign according to our data. Variant chr18-62074825-G-GA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 472221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0638 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.2577-5dupT		splice_region intron	N/A	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.2577-5dupT		splice_region intron	N/A	NP_001425825.1
	PIGN	NM_012327.6		c.2577-5dupT		splice_region intron	N/A	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.2577-5dupT		splice_region intron	N/A	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.2577-5dupT		splice_region intron	N/A	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.*545-5dupT		splice_region intron	N/A	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes AF: 0.00978 AC: 1467 AN: 150064 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00296

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000862

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.0698

Gnomad SAS AF: 0.00673

Gnomad FIN AF: 0.0710

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00301

Gnomad OTH AF: 0.00828

GnomAD2 exomes AF: 0.0141 AC: 2956 AN: 208964 AF XY: 0.0140

Gnomad AFR exome AF: 0.00372

Gnomad AMR exome AF: 0.00141

Gnomad ASJ exome AF: 0.00419

Gnomad EAS exome AF: 0.0669

Gnomad FIN exome AF: 0.0669

Gnomad NFE exome AF: 0.00375

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.00668 AC: 9446 AN: 1414862 Hom.: 174 Cov.: 26 AF XY: 0.00652 AC XY: 4589 AN XY: 704186

African (AFR) AF: 0.00301 AC: 97 AN: 32278

American (AMR) AF: 0.00128 AC: 55 AN: 42904

Ashkenazi Jewish (ASJ) AF: 0.00479 AC: 121 AN: 25252

East Asian (EAS) AF: 0.0714 AC: 2747 AN: 38454

South Asian (SAS) AF: 0.00329 AC: 271 AN: 82276

European-Finnish (FIN) AF: 0.0629 AC: 3291 AN: 52350

Middle Eastern (MID) AF: 0.00178 AC: 10 AN: 5624

European-Non Finnish (NFE) AF: 0.00219 AC: 2358 AN: 1077260

Other (OTH) AF: 0.00848 AC: 496 AN: 58464

GnomAD4 genome AF: 0.00976 AC: 1466 AN: 150178 Hom.: 41 Cov.: 32 AF XY: 0.0131 AC XY: 959 AN XY: 73228

African (AFR) AF: 0.00295 AC: 121 AN: 40984

American (AMR) AF: 0.000861 AC: 13 AN: 15092

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3458

East Asian (EAS) AF: 0.0698 AC: 358 AN: 5130

South Asian (SAS) AF: 0.00694 AC: 33 AN: 4754

European-Finnish (FIN) AF: 0.0710 AC: 713 AN: 10044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00301 AC: 203 AN: 67448

Other (OTH) AF: 0.00771 AC: 16 AN: 2076

Alfa AF: 0.00692 Hom.: 3

Bravo AF: 0.00450

ClinVar

ClinVar submissions

Significance: Benign/Likely 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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.073
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs138671843;

hg19: chr18-59742058;

COSMIC: COSV62951037;