rs200133111

Variant names:

• chr1-77161333-C-A
• rs200133111
• NM_005482.3:c.775G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-77161333-C-A
• chr1-77161333-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005482.3(PIGK):​c.775G>T​(p.Glu259*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PIGK NM_005482.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.28
• Publications: 3 publications found

Genes affected

PIGK (HGNC:8965): (phosphatidylinositol glycan anchor biosynthesis class K) This gene encodes a member of the cysteine protease family C13 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 a member of the multisubunit enzyme, GPI transamidase and is thought to be its enzymatic component. GPI transamidase mediates GPI anchoring in the endoplasmic reticulum, by catalyzing the transfer of fully assembled GPI units to proteins. [provided by RefSeq, Jul 2008]

PIGK Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005482.3. 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
	PIGK	NM_005482.3	MANE Select	c.775G>T	p.Glu259*	stop_gained	Exon 8 of 11	NP_005473.1	Q92643-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGK	ENST00000370812.8	TSL:1 MANE Select	c.775G>T	p.Glu259*	stop_gained	Exon 8 of 11	ENSP00000359848.3	Q92643-1
	PIGK	ENST00000359130.1	TSL:1	c.775G>T	p.Glu259*	stop_gained	Exon 8 of 9	ENSP00000352041.1	A6NEM5
	PIGK	ENST00000445065.5	TSL:1	c.493G>T	p.Glu165*	stop_gained	Exon 5 of 8	ENSP00000388854.1	B1AK81

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1449266 Hom.: 0 Cov.: 26 AF XY: 0.00000139 AC XY: 1 AN XY: 721942

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33224

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 86016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1100738

Other (OTH) AF: 0.00 AC: 0 AN: 59920

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0245704), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.3
Vest4		0.54
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=4/196	disease causing

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: rs200133111; hg19: chr1-77627018; COSMIC: COSV63061654;