rs587777186

Variant names:

• chr18-62146023-A-G
• rs587777186
• NM_176787.5:c.808T>C

Your query was ambiguous. Multiple possible variants found:

• chr18-62146023-A-G
• chr18-62146023-A-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PM1 PM2 PP5_Moderate

The NM_176787.5(PIGN):​c.808T>C​(p.Ser270Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000154 in 1,297,314 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000932955: Experimental studies have shown that this missense change affects PIGN function (PMID:24253414).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S270T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: PIGN NM_176787.5 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.74
• Publications: 12 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: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000932955: Experimental studies have shown that this missense change affects PIGN function (PMID: 24253414).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_176787.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-62146023-A-G is Pathogenic according to our data. Variant chr18-62146023-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 101047.Status of the report is criteria_provided_single_submitter, 1 stars.

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.808T>C	p.Ser270Pro	missense splice_region	Exon 10 of 31	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.808T>C	p.Ser270Pro	missense splice_region	Exon 10 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.808T>C	p.Ser270Pro	missense splice_region	Exon 9 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.808T>C	p.Ser270Pro	missense splice_region	Exon 10 of 31	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.808T>C	p.Ser270Pro	missense splice_region	Exon 9 of 30	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.808T>C		splice_region non_coding_transcript_exon	Exon 8 of 29	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1297314 Hom.: 0 Cov.: 18 AF XY: 0.00000307 AC XY: 2 AN XY: 650918

African (AFR) AF: 0.00 AC: 0 AN: 29116

American (AMR) AF: 0.00 AC: 0 AN: 36176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23600

East Asian (EAS) AF: 0.0000516 AC: 2 AN: 38730

South Asian (SAS) AF: 0.00 AC: 0 AN: 75460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5330

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 981872

Other (OTH) AF: 0.00 AC: 0 AN: 54430

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Multiple congenital anomalies-hypotonia-seizures syndrome 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		2.7
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.013	D
Polyphen		0.97	D
Vest4		0.51
MutPred		0.48		Loss of glycosylation at S270 (P = 0.051)
MVP		0.62
MPC		0.18
ClinPred		0.96	D
GERP RS		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.82
Mutation Taster		=29/71	disease causing (ClinVar)

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: rs587777186; hg19: chr18-59813256;