chr18-62143306-C-G

Variant names:

• chr18-62143306-C-G
• rs587777187
• NM_176787.5:c.963G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_176787.5(PIGN):​c.963G>C​(p.Gln321His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000745 in 1,341,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q321Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: PIGN NM_176787.5 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.94
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet, ClinGen, PanelApp Australia
• Fryns syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5	c.963G>C	p.Gln321His	missense_variant, splice_region_variant	Exon 11 of 31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.963G>C	p.Gln321His	missense_variant, splice_region_variant	Exon 11 of 31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.963G>C	p.Gln321His	missense_variant, splice_region_variant	Exon 10 of 30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.963G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.45e-7 AC: 1 AN: 1341494 Hom.: 0 Cov.: 21 AF XY: 0.00000150 AC XY: 1 AN XY: 667804

African (AFR) AF: 0.0000324 AC: 1 AN: 30890

American (AMR) AF: 0.00 AC: 0 AN: 39616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24796

East Asian (EAS) AF: 0.00 AC: 0 AN: 37644

South Asian (SAS) AF: 0.00 AC: 0 AN: 78624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5532

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1017294

Other (OTH) AF: 0.00 AC: 0 AN: 56270

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;D;D;D;.;.;.;.;.;D;.;.;D;.;D;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;.;.;.;.;.;D;.;T;D;.;D;T;.;D;D;D;D;.;.;D;T;D;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	3.7	H;.;H;H;H;.;.;.;.;.;H;.;.;H;.;H;.;.;.;.;.;.;.;.
PhyloP100		5.9
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.0	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;D;D;.;.;.;.;.;D;.;.;D;.;D;.;.;.;.;.;.;.;.
Vest4		0.97
MutPred		0.81		Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);.;.;Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);Loss of stability (P = 0.2752);
MVP		0.80
MPC		0.19
ClinPred		1.0	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.91
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.80		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777187; hg19: chr18-59810539;