1-172442066-G-C
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP3BS1_SupportingBS2
The NM_153747.2(PIGC):āc.557C>Gā(p.Ser186Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,614,244 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00013 ( 0 hom., cov: 32)
Exomes š: 0.000056 ( 2 hom. )
Consequence
PIGC
NM_153747.2 missense
NM_153747.2 missense
Scores
6
7
5
Clinical Significance
Conservation
PhyloP100: 9.39
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 Likely_benign. 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
PP3
MetaRNN computational evidence supports a deleterious effect, 0.801
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000561 (82/1461886) while in subpopulation MID AF= 0.00277 (16/5768). AF 95% confidence interval is 0.00174. There are 2 homozygotes in gnomad4_exome. There are 53 alleles in male gnomad4_exome subpopulation. Median coverage is 39. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIGC | NM_153747.2 | c.557C>G | p.Ser186Cys | missense_variant | 2/2 | ENST00000344529.5 | |
C1orf105 | NM_139240.4 | c.22-3007G>C | intron_variant | ENST00000367727.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIGC | ENST00000344529.5 | c.557C>G | p.Ser186Cys | missense_variant | 2/2 | 1 | NM_153747.2 | P1 | |
C1orf105 | ENST00000367727.9 | c.22-3007G>C | intron_variant | 1 | NM_139240.4 | P1 | |||
PIGC | ENST00000484368.1 | n.96+1922C>G | intron_variant, non_coding_transcript_variant | 1 | |||||
PIGC | ENST00000367728.1 | c.557C>G | p.Ser186Cys | missense_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152240Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251442Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135894
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GnomAD4 exome AF: 0.0000561 AC: 82AN: 1461886Hom.: 2 Cov.: 39 AF XY: 0.0000729 AC XY: 53AN XY: 727244
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GnomAD4 genome AF: 0.000131 AC: 20AN: 152358Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74512
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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 09, 2021 | The c.557C>G (p.S186C) alteration is located in exon 2 (coding exon 1) of the PIGC gene. This alteration results from a C to G substitution at nucleotide position 557, causing the serine (S) at amino acid position 186 to be replaced by a cysteine (C). 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 | Sep 24, 2021 | This sequence change replaces serine with cysteine at codon 186 of the PIGC protein (p.Ser186Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs140958278, ExAC 0.01%). This variant has not been reported in the literature in individuals with PIGC-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
0.57
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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