rs12326381

Variant names:

• chr18-62102800-C-T
• rs12326381
• NM_176787.5:c.1962G>A

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.1962G>A​(p.Leu654Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,456,732 control chromosomes in the GnomAD database, including 36,512 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. L654L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.17 (2947 hom., cov: 31)
  • Exomes 𝑓: 0.22 (33565 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.52
• 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• 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=-0.8).
• BP6: Variant 18-62102800-C-T is Benign according to our data. Variant chr18-62102800-C-T is described in ClinVar as Benign. ClinVar VariationId is 403301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.52 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	NM_176787.5	MANE Select	c.1962G>A	p.Leu654Leu	synonymous	Exon 21 of 31	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.1962G>A	p.Leu654Leu	synonymous	Exon 21 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.1962G>A	p.Leu654Leu	synonymous	Exon 20 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.1962G>A	p.Leu654Leu	synonymous	Exon 21 of 31	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.1962G>A	p.Leu654Leu	synonymous	Exon 20 of 30	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.1962G>A		non_coding_transcript_exon	Exon 19 of 29	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25968 AN: 152014 Hom.: 2946 Cov.: 31

Gnomad AFR AF: 0.0499

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.192

GnomAD2 exomes AF: 0.166 AC: 29527 AN: 177866 AF XY: 0.166

Gnomad AFR exome AF: 0.0406

Gnomad AMR exome AF: 0.0996

Gnomad ASJ exome AF: 0.248

Gnomad EAS exome AF: 0.00272

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.217 AC: 283249 AN: 1304598 Hom.: 33565 Cov.: 18 AF XY: 0.216 AC XY: 140140 AN XY: 649912

African (AFR) AF: 0.0401 AC: 1203 AN: 30008

American (AMR) AF: 0.111 AC: 3954 AN: 35746

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 5974 AN: 24448

East Asian (EAS) AF: 0.00140 AC: 52 AN: 37144

South Asian (SAS) AF: 0.111 AC: 8348 AN: 75418

European-Finnish (FIN) AF: 0.234 AC: 11831 AN: 50592

Middle Eastern (MID) AF: 0.239 AC: 1310 AN: 5484

European-Non Finnish (NFE) AF: 0.242 AC: 239404 AN: 990544

Other (OTH) AF: 0.202 AC: 11173 AN: 55214

GnomAD4 genome AF: 0.171 AC: 25975 AN: 152134 Hom.: 2947 Cov.: 31 AF XY: 0.168 AC XY: 12491 AN XY: 74374

African (AFR) AF: 0.0497 AC: 2065 AN: 41526

American (AMR) AF: 0.152 AC: 2327 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 869 AN: 3468

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5182

South Asian (SAS) AF: 0.108 AC: 520 AN: 4814

European-Finnish (FIN) AF: 0.245 AC: 2595 AN: 10582

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

European-Non Finnish (NFE) AF: 0.248 AC: 16852 AN: 67970

Other (OTH) AF: 0.194 AC: 409 AN: 2106

Alfa AF: 0.236 Hom.: 7529

Bravo AF: 0.159

Asia WGS AF: 0.0800 AC: 280 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (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	-0.80
CADD	Benign	0.36
DANN	Benign	0.45
PhyloP100		-2.5
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs12326381; hg19: chr18-59770033; COSMIC: COSV62952137; COSMIC: COSV62952137;