ENST00000026218.9:c.2002T>C

Variant names:

• chr16-583353-T-C
• rs710924
• ENST00000026218.9:c.2002T>C
• PIGQ p.Cys668Arg

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000026218.9(PIGQ):​c.2002T>C​(p.Cys668Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 1,611,930 control chromosomes in the GnomAD database, including 166,855 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C668F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.46 (16177 hom., cov: 33)
  • Exomes 𝑓: 0.45 (150678 hom.)
• Consequence: PIGQ ENST00000026218.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.53
• Publications: 27 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: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.912361E-6).
• BP6: Variant 16-583353-T-C is Benign according to our data. Variant chr16-583353-T-C is described in ClinVar as Benign. ClinVar VariationId is 1277846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000026218.9. 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.*318T>C		3_prime_UTR	Exon 11 of 11	NP_004195.2
	PIGQ	NM_148920.4		c.2002T>C	p.Cys668Arg	missense	Exon 10 of 10	NP_683721.1	Q9BRB3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGQ	ENST00000026218.9	TSL:1	c.2002T>C	p.Cys668Arg	missense	Exon 10 of 10	ENSP00000026218.5	Q9BRB3-1
	PIGQ	ENST00000321878.10	TSL:1 MANE Select	c.*318T>C		3_prime_UTR	Exon 11 of 11	ENSP00000326674.6	Q9BRB3-2
	PIGQ	ENST00000854227.1		c.*318T>C		3_prime_UTR	Exon 12 of 12	ENSP00000524286.1

Frequencies

GnomAD3 genomes AF: 0.457 AC: 69176 AN: 151462 Hom.: 16148 Cov.: 33

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.637

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.503

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.404

GnomAD2 exomes AF: 0.488 AC: 121834 AN: 249866 AF XY: 0.487

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.559

Gnomad ASJ exome AF: 0.374

Gnomad EAS exome AF: 0.617

Gnomad FIN exome AF: 0.507

Gnomad NFE exome AF: 0.419

Gnomad OTH exome AF: 0.433

GnomAD4 exome AF: 0.448 AC: 654291 AN: 1460354 Hom.: 150678 Cov.: 58 AF XY: 0.452 AC XY: 328380 AN XY: 726506

African (AFR) AF: 0.472 AC: 15803 AN: 33472

American (AMR) AF: 0.549 AC: 24553 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 9960 AN: 26134

East Asian (EAS) AF: 0.667 AC: 26472 AN: 39700

South Asian (SAS) AF: 0.621 AC: 53573 AN: 86256

European-Finnish (FIN) AF: 0.513 AC: 26707 AN: 52092

Middle Eastern (MID) AF: 0.327 AC: 1885 AN: 5768

European-Non Finnish (NFE) AF: 0.421 AC: 468557 AN: 1111848

Other (OTH) AF: 0.444 AC: 26781 AN: 60370

GnomAD4 genome AF: 0.457 AC: 69256 AN: 151576 Hom.: 16177 Cov.: 33 AF XY: 0.465 AC XY: 34447 AN XY: 74048

African (AFR) AF: 0.471 AC: 19477 AN: 41310

American (AMR) AF: 0.479 AC: 7311 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1314 AN: 3464

East Asian (EAS) AF: 0.637 AC: 3263 AN: 5126

South Asian (SAS) AF: 0.628 AC: 3022 AN: 4812

European-Finnish (FIN) AF: 0.503 AC: 5291 AN: 10516

Middle Eastern (MID) AF: 0.346 AC: 101 AN: 292

European-Non Finnish (NFE) AF: 0.417 AC: 28280 AN: 67786

Other (OTH) AF: 0.411 AC: 867 AN: 2110

Alfa AF: 0.426 Hom.: 7178

Bravo AF: 0.451

Asia WGS AF: 0.658 AC: 2291 AN: 3478

EpiCase AF: 0.395

EpiControl AF: 0.388

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.6
DANN	Benign	0.49
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0000069	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.015
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.48	T
Varity_R		0.48
gMVP		0.024
Mutation Taster		=98/2	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs710924;

hg19: chr16-633353;

COSMIC: COSV50313344;

COSMIC: COSV50313344;