rs1442463365

Variant names:

• chr9-123356289-AC-A
• rs1442463365
• NM_173689.7:c.34delC

Your query was ambiguous. Multiple possible variants found:

• chr9-123356289-AC-A
• chr9-123356289-AC-ACC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_173689.7(CRB2):​c.34delC​(p.Gln12ArgfsTer130) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,386,386 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CRB2 NM_173689.7 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.237
• Publications: 0 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 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 43 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.34delC	p.Gln12ArgfsTer130	frameshift	Exon 1 of 13	NP_775960.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB2	ENST00000373631.8	TSL:1 MANE Select	c.34delC	p.Gln12ArgfsTer130	frameshift	Exon 1 of 13	ENSP00000362734.3	Q5IJ48-1
	CRB2	ENST00000896215.1		c.34delC	p.Gln12ArgfsTer130	frameshift	Exon 1 of 13	ENSP00000566274.1
	CRB2	ENST00000359999.7	TSL:2	c.34delC	p.Gln12ArgfsTer130	frameshift	Exon 1 of 10	ENSP00000353092.3	Q5IJ48-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1386386 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 683902

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31058

American (AMR) AF: 0.00 AC: 0 AN: 33902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24894

East Asian (EAS) AF: 0.00 AC: 0 AN: 35362

South Asian (SAS) AF: 0.00 AC: 0 AN: 78392

European-Finnish (FIN) AF: 0.0000446 AC: 2 AN: 44852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5440

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075030

Other (OTH) AF: 0.00 AC: 0 AN: 57456

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.24

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

Other links and lift over

dbSNP: rs1442463365; hg19: chr9-126118568;