rs200750917

Variant names:

• chr18-62084586-T-C
• rs200750917
• NM_176787.5:c.2447A>G

Your query was ambiguous. Multiple possible variants found:

• chr18-62084586-T-C
• chr18-62084586-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_176787.5(PIGN):​c.2447A>G​(p.Tyr816Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000264 in 1,556,908 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y816S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.81
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

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.2447A>G	p.Tyr816Cys	missense	Exon 27 of 31	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.2447A>G	p.Tyr816Cys	missense	Exon 27 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.2447A>G	p.Tyr816Cys	missense	Exon 26 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.2447A>G	p.Tyr816Cys	missense	Exon 27 of 31	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.2447A>G	p.Tyr816Cys	missense	Exon 26 of 30	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.*415A>G		non_coding_transcript_exon	Exon 25 of 29	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000581 AC: 10 AN: 172252 AF XY: 0.0000772

Gnomad AFR exome AF: 0.000105

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000213

GnomAD4 exome AF: 0.000280 AC: 394 AN: 1404870 Hom.: 0 Cov.: 28 AF XY: 0.000280 AC XY: 194 AN XY: 693988

African (AFR) AF: 0.00 AC: 0 AN: 31838

American (AMR) AF: 0.00 AC: 0 AN: 36988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25218

East Asian (EAS) AF: 0.00 AC: 0 AN: 36600

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79500

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.000352 AC: 380 AN: 1080418

Other (OTH) AF: 0.000188 AC: 11 AN: 58372

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152038 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74266

African (AFR) AF: 0.0000483 AC: 2 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000175 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000613 AC: 5

ExAC AF: 0.0000872 AC: 10

ClinVar

ClinVar submissions

Significance: Uncertain significance

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.48
Sift	Benign	0.16	T
Sift4G	Benign	0.096	T
Polyphen		1.0	D
Vest4		0.99
MVP		0.88
MPC		0.21
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.35
gMVP		0.70
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200750917; hg19: chr18-59751819;