NM_173689.7:c.3089_3104dupGGCCCGGCGCGGCCCC

Variant summary

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

The NM_173689.7(CRB2):​c.3089_3104dupGGCCCGGCGCGGCCCC​(p.Gly1036AlafsTer43) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,374,380 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P1035PGAAP?) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0017 ( 0 hom. )

Consequence

CRB2
NM_173689.7 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 0.602
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 9-123373608-T-TGGCGCGGCCCCGGCCC is Pathogenic according to our data. Variant chr9-123373608-T-TGGCGCGGCCCCGGCCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CRB2NM_173689.7 linkc.3089_3104dupGGCCCGGCGCGGCCCC p.Gly1036AlafsTer43 frameshift_variant Exon 10 of 13 ENST00000373631.8 NP_775960.4 Q5IJ48-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CRB2ENST00000373631.8 linkc.3089_3104dupGGCCCGGCGCGGCCCC p.Gly1036AlafsTer43 frameshift_variant Exon 10 of 13 1 NM_173689.7 ENSP00000362734.3 Q5IJ48-1
CRB2ENST00000359999.7 linkc.3089_3104dupGGCCCGGCGCGGCCCC p.Gly1036AlafsTer43 frameshift_variant Exon 10 of 10 2 ENSP00000353092.3 Q5IJ48-2
CRB2ENST00000460253.1 linkn.2093_2108dupGGCCCGGCGCGGCCCC non_coding_transcript_exon_variant Exon 5 of 9 2 ENSP00000435279.1 Q5IJ48-3

Frequencies

GnomAD3 genomes
AF:
0.00104
AC:
157
AN:
151594
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.000508
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000263
Gnomad ASJ
AF:
0.000289
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00103
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00186
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00168
AC:
2053
AN:
1222678
Hom.:
0
Cov.:
39
AF XY:
0.00159
AC XY:
954
AN XY:
598778
show subpopulations
Gnomad4 AFR exome
AF:
0.000288
Gnomad4 AMR exome
AF:
0.000235
Gnomad4 ASJ exome
AF:
0.000228
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000295
Gnomad4 FIN exome
AF:
0.0000664
Gnomad4 NFE exome
AF:
0.00197
Gnomad4 OTH exome
AF:
0.00102
GnomAD4 genome
AF:
0.00103
AC:
157
AN:
151702
Hom.:
0
Cov.:
34
AF XY:
0.000768
AC XY:
57
AN XY:
74176
show subpopulations
Gnomad4 AFR
AF:
0.000506
Gnomad4 AMR
AF:
0.000263
Gnomad4 ASJ
AF:
0.000289
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00103
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00186
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:7
-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 11, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly1036Alafs*43) 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). This variant is present in population databases (no rsID available, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of CRB2-related conditions (PMID: 25557779, 27004616). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 180701). For these reasons, this variant has been classified as Pathogenic. -

Apr 26, 2022
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 29, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Frame-shift 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: 34670123, 32581362, 26925547, 31294511, 25557779, 27004616, 36071576, 36803301) -

Oct 05, 2017
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

CRB2-related disorder Pathogenic:1
-
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This frameshifting variant in exon 10 of 13 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in individuals with cerebral ventriculomegaly and nephrosis (PMID: 26925547, 27004616, 25557779). The c.3089_3104dup (p.Gly1036AlafsTer43) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.09% (28/30574) and is absent in the homozygous state, thus it is presumed to be rare. Based on the available evidence, the c.3089_3104dup (p.Gly1036AlafsTer43) variant is classified as Likely Pathogenic. -

Inborn genetic diseases Pathogenic:1
Nov 05, 2021
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3089_3104dup16 (p.G1036Afs*43) alteration, located in exon 10 (coding exon 10) of the CRB2 gene, consists of a duplication of GGCCCGGCGCGGCCCC at position 3089, causing a translational frameshift with a predicted alternate stop codon after 43 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant has been reported as compound heterozygous with CRB2 missense variants in two individuals with CRB2-related disease (Ebarasi, 2015; Lamont, 2016). Based on the available evidence, this alteration is classified as pathogenic. -

Steroid-resistant nephrotic syndrome Pathogenic:1
-
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Focal segmental glomerulosclerosis 9 Pathogenic:1
Jan 08, 2015
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Ventriculomegaly-cystic kidney disease;C4015555:Focal segmental glomerulosclerosis 9 Pathogenic:1
Jan 17, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs879255251; hg19: chr9-126135887; API