chr1-77092381-A-G

Variant names:

• chr1-77092381-A-G
• rs1653320341
• NM_005482.3:c.1181T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005482.3(PIGK):​c.1181T>C​(p.Ile394Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000748 in 1,336,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: PIGK NM_005482.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.59
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22417116).

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.1181T>C	p.Ile394Thr	missense	Exon 11 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.1181T>C	p.Ile394Thr	missense	Exon 11 of 11	ENSP00000359848.3	Q92643-1
	PIGK	ENST00000445065.5	TSL:1	c.899T>C	p.Ile300Thr	missense	Exon 8 of 8	ENSP00000388854.1	B1AK81
	PIGK	ENST00000858231.1		c.1262T>C	p.Ile421Thr	missense	Exon 12 of 12	ENSP00000528290.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.48e-7 AC: 1 AN: 1336792 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 670526

African (AFR) AF: 0.00 AC: 0 AN: 30072

American (AMR) AF: 0.00 AC: 0 AN: 39562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24930

East Asian (EAS) AF: 0.00 AC: 0 AN: 38588

South Asian (SAS) AF: 0.00 AC: 0 AN: 78916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1009934

Other (OTH) AF: 0.0000178 AC: 1 AN: 56050

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000624 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T
Eigen	Benign	0.050
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M
PhyloP100		8.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.67	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.42	B
Vest4		0.46
MutPred		0.39		Gain of disorder (P = 0.0135)
MVP		0.38
MPC		0.24
ClinPred		0.85	D
GERP RS		4.3
Varity_R		0.24
gMVP		0.68
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1653320341; hg19: chr1-77558066;