18-62113191-A-G

Variant names:

• chr18-62113191-A-G
• rs17714875
• NM_176787.5:c.1377T>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.1377T>C​(p.Ser459Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,610,870 control chromosomes in the GnomAD database, including 43,064 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. S459S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.17 (2930 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40134 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.789
• Publications: 17 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=-0.5).
• BP6: Variant 18-62113191-A-G is Benign according to our data. Variant chr18-62113191-A-G is described in ClinVar as Benign. ClinVar VariationId is 403303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.789 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.1377T>C	p.Ser459Ser	synonymous	Exon 16 of 31	NP_789744.1
	PIGN	NM_001438896.1		c.1377T>C	p.Ser459Ser	synonymous	Exon 16 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.1377T>C	p.Ser459Ser	synonymous	Exon 15 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.1377T>C	p.Ser459Ser	synonymous	Exon 16 of 31	ENSP00000492233.1
	PIGN	ENST00000400334.7	TSL:1	c.1377T>C	p.Ser459Ser	synonymous	Exon 15 of 30	ENSP00000383188.2
	PIGN	ENST00000638424.1	TSL:5	n.1377T>C		non_coding_transcript_exon	Exon 14 of 29	ENSP00000491963.1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25712 AN: 152060 Hom.: 2929 Cov.: 32

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.00500

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.192

GnomAD2 exomes AF: 0.177 AC: 43791 AN: 246832 AF XY: 0.181

Gnomad AFR exome AF: 0.0407

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.00281

Gnomad FIN exome AF: 0.240

Gnomad NFE exome AF: 0.243

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.225 AC: 328421 AN: 1458692 Hom.: 40134 Cov.: 32 AF XY: 0.223 AC XY: 161916 AN XY: 725620

African (AFR) AF: 0.0377 AC: 1262 AN: 33442

American (AMR) AF: 0.113 AC: 5043 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 6502 AN: 26076

East Asian (EAS) AF: 0.00142 AC: 56 AN: 39508

South Asian (SAS) AF: 0.115 AC: 9878 AN: 86100

European-Finnish (FIN) AF: 0.236 AC: 12584 AN: 53244

Middle Eastern (MID) AF: 0.243 AC: 1396 AN: 5746

European-Non Finnish (NFE) AF: 0.252 AC: 279147 AN: 1109808

Other (OTH) AF: 0.208 AC: 12553 AN: 60256

GnomAD4 genome AF: 0.169 AC: 25717 AN: 152178 Hom.: 2930 Cov.: 32 AF XY: 0.166 AC XY: 12381 AN XY: 74390

African (AFR) AF: 0.0443 AC: 1842 AN: 41568

American (AMR) AF: 0.152 AC: 2319 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 867 AN: 3470

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5184

South Asian (SAS) AF: 0.107 AC: 518 AN: 4822

European-Finnish (FIN) AF: 0.245 AC: 2589 AN: 10568

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16835 AN: 67956

Other (OTH) AF: 0.194 AC: 410 AN: 2116

Alfa AF: 0.220 Hom.: 5808

Bravo AF: 0.157

Asia WGS AF: 0.0810 AC: 283 AN: 3474

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	-0.50
CADD	Benign	5.3
DANN	Benign	0.74
PhyloP100		0.79
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17714875; hg19: chr18-59780424; COSMIC: COSV62950788; COSMIC: COSV62950788;