2-120797400-ACCCGGGTAAAAAGG-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_001374353.1(GLI2):c.83_96del(p.Pro28LeufsTer33) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000274 in 1,460,288 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
GLI2
NM_001374353.1 frameshift
NM_001374353.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.83
Genes affected
GLI2 (HGNC:4318): (GLI family zinc finger 2) This gene encodes a protein which belongs to the C2H2-type zinc finger protein subclass of the Gli family. Members of this subclass are characterized as transcription factors which bind DNA through zinc finger motifs. These motifs contain conserved H-C links. Gli family zinc finger proteins are mediators of Sonic hedgehog (Shh) signaling and they are implicated as potent oncogenes in the embryonal carcinoma cell. The protein encoded by this gene localizes to the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. The encoded protein is associated with several phenotypes- Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, postaxial polydactyly types A1 and B. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 39 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLI2 | NM_001374353.1 | c.83_96del | p.Pro28LeufsTer33 | frameshift_variant | 2/14 | ENST00000361492.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLI2 | ENST00000361492.9 | c.83_96del | p.Pro28LeufsTer33 | frameshift_variant | 2/14 | 1 | NM_001374353.1 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
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32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251208Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135886
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460288Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 726540
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GnomAD4 genome ? Cov.: 32
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Bravo
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 10, 2022 | Reported in one individual with a neurodevelopmental disorder (Stessman et al., 2017); however, detailed clinical information was not provided; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28191889) - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at