rs879255251
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_173689.7(CRB2):c.3089_3104del(p.Arg1030LeufsTer106) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000386 in 1,374,404 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000037 ( 0 hom. )
Consequence
CRB2
NM_173689.7 frameshift
NM_173689.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.86
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 9-123373608-TGGCGCGGCCCCGGCCC-T is Pathogenic according to our data. Variant chr9-123373608-TGGCGCGGCCCCGGCCC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1324169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-123373608-TGGCGCGGCCCCGGCCC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRB2 | NM_173689.7 | c.3089_3104del | p.Arg1030LeufsTer106 | frameshift_variant | 10/13 | ENST00000373631.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRB2 | ENST00000373631.8 | c.3089_3104del | p.Arg1030LeufsTer106 | frameshift_variant | 10/13 | 1 | NM_173689.7 | P1 | |
CRB2 | ENST00000359999.7 | c.3089_3104del | p.Arg1030LeufsTer138 | frameshift_variant | 10/10 | 2 | |||
CRB2 | ENST00000460253.1 | c.2093_2108del | p.Arg698LeufsTer106 | frameshift_variant, NMD_transcript_variant | 5/9 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000528 AC: 8AN: 151596Hom.: 0 Cov.: 34
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GnomAD4 exome AF: 0.0000368 AC: 45AN: 1222808Hom.: 0 AF XY: 0.0000434 AC XY: 26AN XY: 598848
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GnomAD4 genome ? AF: 0.0000528 AC: 8AN: 151596Hom.: 0 Cov.: 34 AF XY: 0.0000405 AC XY: 3AN XY: 74058
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 04, 2020 | - - |
CRB2-related condition Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 14, 2022 | The CRB2 c.3089_3104del16 variant is predicted to result in a frameshift and premature protein termination (p.Arg1030Leufs*106). This variant has been reported in the compound heterozygous state in a fetus with ventriculomegaly, hydrocephalus, and echogenic kidneys (Zhang et al. 2020. PubMed ID: 32051522). This variant is reported in 1 of 59,000 alleles in gnomAD: However, the quality of this call is questionable and should be interpreted with caution (http://gnomad.broadinstitute.org/variant/9-126135887-TGGCGCGGCCCCGGCCC-T). Frameshift variants in CRB2 are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at