16-582262-C-T

Variant names:

• chr16-582262-C-T
• rs144613953
• NM_004204.5:c.1546C>T

Variant summary

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

The NM_004204.5(PIGQ):​c.1546C>T​(p.Arg516Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000342 in 1,606,902 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. R516H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: PIGQ NM_004204.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.17
• Publications: 4 publications found

Genes affected

PIGQ (HGNC:14135): (phosphatidylinositol glycan anchor biosynthesis class Q) This gene is involved in the first step 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 gene encodes a N-acetylglucosaminyl transferase component that is part of the complex that catalyzes transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

PIGQ Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 77

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD 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_004204.5. 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
	PIGQ	NM_004204.5	MANE Select	c.1546C>T	p.Arg516Cys	missense	Exon 10 of 11	NP_004195.2
	PIGQ	NM_148920.4		c.1532-621C>T		intron	N/A	NP_683721.1	Q9BRB3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGQ	ENST00000321878.10	TSL:1 MANE Select	c.1546C>T	p.Arg516Cys	missense	Exon 10 of 11	ENSP00000326674.6	Q9BRB3-2
	PIGQ	ENST00000026218.9	TSL:1	c.1532-621C>T		intron	N/A	ENSP00000026218.5	Q9BRB3-1
	PIGQ	ENST00000854227.1		c.1708C>T	p.Arg570Cys	missense	Exon 11 of 12	ENSP00000524286.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152244 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000837 AC: 20 AN: 239062 AF XY: 0.0000613

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000500

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000280

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000344 AC: 50 AN: 1454658 Hom.: 0 Cov.: 31 AF XY: 0.0000346 AC XY: 25 AN XY: 723144

African (AFR) AF: 0.0000899 AC: 3 AN: 33362

American (AMR) AF: 0.000472 AC: 21 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39452

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51344

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5756

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1108796

Other (OTH) AF: 0.0000333 AC: 2 AN: 60072

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152244 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74376

African (AFR) AF: 0.0000482 AC: 2 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00000528 Hom.: 26

Bravo AF: 0.0000529

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Epilepsy (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.89	T
PhyloP100		1.2
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.73
MVP		0.59
ClinPred		0.31	T
GERP RS		2.8
Mutation Taster		=85/15	polymorphism

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: rs144613953; hg19: chr16-632262;