9-123373608-TGGCGCGGCCCCGGCCC-TGGCGCGGCCCCGGCCCGGCGCGGCCCCGGCCC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_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:13

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 was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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

AC:

AN:

24274

Gnomad4 AMR exome

AF:

0.000235

AC:

AN:

12772

Gnomad4 ASJ exome

AF:

0.000228

AC:

AN:

17506

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

26936

Gnomad4 SAS exome

AF:

0.000295

AC:

AN:

54162

Gnomad4 FIN exome

AF:

0.0000664

AC:

AN:

30100

Gnomad4 NFE exome

AF:

0.00197

AC:

1970

AN:

1002116

Gnomad4 Remaining exome

AF:

0.00102

AC:

AN:

49906

Heterozygous variant carriers

115

230

344

459

574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

102

204

306

408

510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

AC:

0.000506195

AN:

0.000506195

Gnomad4 AMR

AF:

0.000263

AC:

0.000262674

AN:

0.000262674

Gnomad4 ASJ

AF:

0.000289

AC:

0.000288517

AN:

0.000288517

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00103

AC:

0.00103434

AN:

0.00103434

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00186

AC:

0.00185759

AN:

0.00185759

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000378

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Oct 05, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 26, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

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

- -

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) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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. -

Focal segmental glomerulosclerosis 9

Pathogenic:2

Jan 08, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 28, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

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. -

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. -

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

- -

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

Mutation Taster

=15/185

disease causing (ClinVar)

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