9-123373608-TGGCGCGGCCCCGGCCC-TGGCGCGGCCCCGGCCCGGCGCGGCCCCGGCCC

Variant names:

• chr9-123373608-T-TGGCGCGGCCCCGGCCC
• rs879255251
• NM_173689.7:c.3089_3104dupGGCCCGGCGCGGCCCC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 0.602
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• ventriculomegaly-cystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 180701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173689.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB2	NM_173689.7	MANE Select	c.3089_3104dupGGCCCGGCGCGGCCCC	p.Gly1036AlafsTer43	frameshift	Exon 10 of 13	NP_775960.4
	CRB2	NR_104603.2		n.2203_2218dupGGCCCGGCGCGGCCCC		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB2	ENST00000373631.8	TSL:1 MANE Select	c.3089_3104dupGGCCCGGCGCGGCCCC	p.Gly1036AlafsTer43	frameshift	Exon 10 of 13	ENSP00000362734.3	Q5IJ48-1
	CRB2	ENST00000896215.1		c.3062_3077dupGGCCCGGCGCGGCCCC	p.Gly1027AlafsTer43	frameshift	Exon 10 of 13	ENSP00000566274.1
	CRB2	ENST00000359999.7	TSL:2	c.3089_3104dupGGCCCGGCGCGGCCCC	p.Gly1036AlafsTer43	frameshift	Exon 10 of 10	ENSP00000353092.3	Q5IJ48-2

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 157 AN: 151594 Hom.: 0 Cov.: 34

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

African (AFR) AF: 0.000288 AC: 7 AN: 24274

American (AMR) AF: 0.000235 AC: 3 AN: 12772

Ashkenazi Jewish (ASJ) AF: 0.000228 AC: 4 AN: 17506

East Asian (EAS) AF: 0.00 AC: 0 AN: 26936

South Asian (SAS) AF: 0.000295 AC: 16 AN: 54162

European-Finnish (FIN) AF: 0.0000664 AC: 2 AN: 30100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4906

European-Non Finnish (NFE) AF: 0.00197 AC: 1970 AN: 1002116

Other (OTH) AF: 0.00102 AC: 51 AN: 49906

GnomAD4 genome AF: 0.00103 AC: 157 AN: 151702 Hom.: 0 Cov.: 34 AF XY: 0.000768 AC XY: 57 AN XY: 74176

African (AFR) AF: 0.000506 AC: 21 AN: 41486

American (AMR) AF: 0.000263 AC: 4 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00186 AC: 126 AN: 67830

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000378 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
2	-	-	Focal segmental glomerulosclerosis 9 (2)
1	-	-	CRB2-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Steroid-resistant nephrotic syndrome (1)
1	-	-	Ventriculomegaly-cystic kidney disease;C4015555:Focal segmental glomerulosclerosis 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.60
Mutation Taster		=15/185	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs879255251; hg19: chr9-126135887;