chr1-172441758-T-G
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_153747.2(PIGC):āc.865A>Cā(p.Lys289Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000575 in 1,565,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 32)
Exomes š: 0.0000042 ( 0 hom. )
Consequence
PIGC
NM_153747.2 missense
NM_153747.2 missense
Scores
3
15
Clinical Significance
Conservation
PhyloP100: 5.67
Genes affected
PIGC (HGNC:8960): (phosphatidylinositol glycan anchor biosynthesis class C) This gene encodes an endoplasmic reticulum associated protein that is involved in glycosylphosphatidylinositol (GPI) lipid anchor biosynthesis. The GPI lipid anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. The encoded protein is one subunit of the GPI N-acetylglucosaminyl (GlcNAc) transferase that transfers GlcNAc to phosphatidylinositol (PI) on the cytoplasmic side of the endoplasmic reticulum. Two alternatively spliced transcripts that encode the same protein have been found for this gene. A pseudogene on chromosome 11 has also been characterized. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM1
In a chain Phosphatidylinositol N-acetylglucosaminyltransferase subunit C (size 296) in uniprot entity PIGC_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_153747.2
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1938467).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIGC | NM_153747.2 | c.865A>C | p.Lys289Gln | missense_variant | 2/2 | ENST00000344529.5 | |
C1orf105 | NM_139240.4 | c.22-3315T>G | intron_variant | ENST00000367727.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIGC | ENST00000344529.5 | c.865A>C | p.Lys289Gln | missense_variant | 2/2 | 1 | NM_153747.2 | P1 | |
C1orf105 | ENST00000367727.9 | c.22-3315T>G | intron_variant | 1 | NM_139240.4 | P1 | |||
PIGC | ENST00000484368.1 | n.96+2230A>C | intron_variant, non_coding_transcript_variant | 1 | |||||
PIGC | ENST00000367728.1 | c.865A>C | p.Lys289Gln | missense_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152226Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000189 AC: 4AN: 211532Hom.: 0 AF XY: 0.0000265 AC XY: 3AN XY: 113216
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GnomAD4 exome AF: 0.00000425 AC: 6AN: 1412954Hom.: 0 Cov.: 30 AF XY: 0.00000573 AC XY: 4AN XY: 698396
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74364
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 30, 2022 | The c.865A>C (p.K289Q) alteration is located in exon 2 (coding exon 1) of the PIGC gene. This alteration results from a A to C substitution at nucleotide position 865, causing the lysine (K) at amino acid position 289 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 12, 2022 | This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 289 of the PIGC protein (p.Lys289Gln). This variant is present in population databases (rs777363797, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PIGC-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
P;P
Vest4
MutPred
Loss of ubiquitination at K289 (P = 0.0134);Loss of ubiquitination at K289 (P = 0.0134);
MVP
MPC
0.15
ClinPred
T
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at