Variant 9-123373608-TGGCGCGGCCCCGGCCC-TGGCGCGGCCCCGGCCCGGCGCGGCCCCGGCCC details in Genebe, Genetics Data Aggregator

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]

CRB2 links:

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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
CRB2	NM_173689.7 link	c.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	UniProt
CRB2	ENST00000373631.8 link	c.3089_3104dupGGCCCGGCGCGGCCCC	p.Gly1036AlafsTer43	frameshift_variant	Exon 10 of 13	1	NM_173689.7	ENSP00000362734.3	Q5IJ48-1
CRB2	ENST00000359999.7 link	c.3089_3104dupGGCCCGGCGCGGCCCC	p.Gly1036AlafsTer43	frameshift_variant	Exon 10 of 10	2		ENSP00000353092.3	Q5IJ48-2
CRB2	ENST00000460253.1 link	n.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.:

Cov.:

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.:

Cov.:

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.:

Cov.:

AF XY:

0.000768

AC XY:

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

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 26, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2025	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2024	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) -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 05, 2021

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. -

CRB2-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

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. -

Steroid-resistant nephrotic syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Focal segmental glomerulosclerosis 9

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 08, 2015

- -

Ventriculomegaly-cystic kidney disease;C4015555:Focal segmental glomerulosclerosis 9

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 17, 2022

- -

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over