9-123356289-A-AC
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_173689.7(CRB2):c.34dup(p.Gln12ProfsTer100) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000721 in 1,386,422 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000072 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CRB2
NM_173689.7 frameshift
NM_173689.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.237
Genes affected
CRB2 (HGNC:18688): (crumbs cell polarity complex component 2) This gene encodes a member of a family of proteins that are components of the Crumbs cell polarity complex. In mammals, members of this family are thought to play a role in many cellular processes in early embryonic development. A similar protein in Drosophila determines apicobasal polarity in embryonic epithelial cells. Mutations in this gene are associated with focal segmental glomerulosclerosis 9, and with ventriculomegaly with cystic kidney disease. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 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 12 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 | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CRB2 | NM_173689.7 | c.34dup | p.Gln12ProfsTer100 | frameshift_variant | 1/13 | ENST00000373631.8 | NP_775960.4 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CRB2 | ENST00000373631.8 | c.34dup | p.Gln12ProfsTer100 | frameshift_variant | 1/13 | 1 | NM_173689.7 | ENSP00000362734 | P1 | |
| CRB2 | ENST00000359999.7 | c.34dup | p.Gln12ProfsTer100 | frameshift_variant | 1/10 | 2 | ENSP00000353092 |
Frequencies
GnomAD3 genomes 0.00000660 AC: 1AN: 151600Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000721 AC: 10AN: 1386422Hom.: 0 Cov.: 32 AF XY: 0.0000102 AC XY: 7AN XY: 683928
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GnomAD4 genome 0.00000660 AC: 1AN: 151600Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74002
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Data not reliable, filtered out with message: AS_VQSR
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
not provided Uncertain:1
| Uncertain significance, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at