rs375072557

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000373631.8(CRB2):​c.2277G>A​(p.Trp759Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000757 in 1,612,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

CRB2
ENST00000373631.8 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.87
Variant links:
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 9-123371419-G-A is Pathogenic according to our data. Variant chr9-123371419-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 180704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-123371419-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CRB2NM_173689.7 linkuse as main transcriptc.2277G>A p.Trp759Ter stop_gained 8/13 ENST00000373631.8 NP_775960.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CRB2ENST00000373631.8 linkuse as main transcriptc.2277G>A p.Trp759Ter stop_gained 8/131 NM_173689.7 ENSP00000362734 P1Q5IJ48-1
CRB2ENST00000359999.7 linkuse as main transcriptc.2277G>A p.Trp759Ter stop_gained 8/102 ENSP00000353092 Q5IJ48-2
CRB2ENST00000460253.1 linkuse as main transcriptc.1281G>A p.Trp427Ter stop_gained, NMD_transcript_variant 3/92 ENSP00000435279 Q5IJ48-3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152190
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000802
AC:
2
AN:
249304
Hom.:
0
AF XY:
0.00000741
AC XY:
1
AN XY:
134956
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000822
AC:
120
AN:
1460090
Hom.:
0
Cov.:
35
AF XY:
0.0000799
AC XY:
58
AN XY:
726346
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000106
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152190
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000489
Hom.:
0
Bravo
AF:
0.0000151
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2021For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of focal segmental glomerulosclerosis (PMID: 25557780). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 180704). This variant is present in population databases (rs375072557, ExAC 0.003%). This sequence change creates a premature translational stop signal (p.Trp759*) in the CRB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CRB2 are known to be pathogenic (PMID: 27942854, 30212996). -
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 26, 2023Observed with a second CRB2 variant on the opposite allele (in trans) in two sibling fetuses with renal microcysts and ventriculomegaly (Slavotinek et al., 2015); Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28425981, 25557780, 36685964, 36549870) -
Ventriculomegaly-cystic kidney disease Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 08, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
43
DANN
Uncertain
1.0
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.96
D
MutationTaster
Benign
1.0
A;A;A
Vest4
0.89
GERP RS
5.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs375072557; hg19: chr9-126133698; API