18-62114567-A-G

Variant names:

• chr18-62114567-A-G
• rs13381627
• NM_176787.5:c.1245T>C

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.1245T>C​(p.Asp415Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 1,505,156 control chromosomes in the GnomAD database, including 39,443 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2949 hom., cov: 31)
  • Exomes 𝑓: 0.22 (36494 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.567
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 18-62114567-A-G is Benign according to our data. Variant chr18-62114567-A-G is described in ClinVar as Benign. ClinVar VariationId is 403304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.567 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.245 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	NM_176787.5	MANE Select	c.1245T>C	p.Asp415Asp	synonymous	Exon 15 of 31	NP_789744.1
	PIGN	NM_001438896.1		c.1245T>C	p.Asp415Asp	synonymous	Exon 15 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.1245T>C	p.Asp415Asp	synonymous	Exon 14 of 30	NP_036459.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	ENST00000640252.2	TSL:1 MANE Select	c.1245T>C	p.Asp415Asp	synonymous	Exon 15 of 31	ENSP00000492233.1
	PIGN	ENST00000400334.7	TSL:1	c.1245T>C	p.Asp415Asp	synonymous	Exon 14 of 30	ENSP00000383188.2
	PIGN	ENST00000638424.1	TSL:5	n.1245T>C		non_coding_transcript_exon	Exon 13 of 29	ENSP00000491963.1

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25936 AN: 151932 Hom.: 2948 Cov.: 31

Gnomad AFR AF: 0.0497

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.00502

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.191

GnomAD2 exomes AF: 0.175 AC: 27254 AN: 155910 AF XY: 0.175

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.00293

Gnomad FIN exome AF: 0.237

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.205

GnomAD4 exome AF: 0.222 AC: 300647 AN: 1353106 Hom.: 36494 Cov.: 24 AF XY: 0.220 AC XY: 147677 AN XY: 669882

African (AFR) AF: 0.0420 AC: 1299 AN: 30960

American (AMR) AF: 0.116 AC: 4104 AN: 35424

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6108 AN: 24792

East Asian (EAS) AF: 0.00132 AC: 47 AN: 35572

South Asian (SAS) AF: 0.113 AC: 8830 AN: 78164

European-Finnish (FIN) AF: 0.236 AC: 11528 AN: 48880

Middle Eastern (MID) AF: 0.240 AC: 1346 AN: 5610

European-Non Finnish (NFE) AF: 0.247 AC: 255837 AN: 1037320

Other (OTH) AF: 0.205 AC: 11548 AN: 56384

GnomAD4 genome AF: 0.171 AC: 25942 AN: 152050 Hom.: 2949 Cov.: 31 AF XY: 0.168 AC XY: 12461 AN XY: 74302

African (AFR) AF: 0.0496 AC: 2060 AN: 41520

American (AMR) AF: 0.152 AC: 2325 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 869 AN: 3472

East Asian (EAS) AF: 0.00522 AC: 27 AN: 5170

South Asian (SAS) AF: 0.108 AC: 518 AN: 4810

European-Finnish (FIN) AF: 0.245 AC: 2579 AN: 10544

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16847 AN: 67960

Other (OTH) AF: 0.194 AC: 406 AN: 2098

Alfa AF: 0.219 Hom.: 7309

Bravo AF: 0.159

Asia WGS AF: 0.0810 AC: 284 AN: 3478

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.24
DANN	Benign	0.28
PhyloP100		-0.57
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: rs13381627; hg19: chr18-59781800; COSMIC: COSV62947744; COSMIC: COSV62947744;