rs992216922

Variant names:

• chr9-123356318-C-T
• rs992216922
• NM_173689.7:c.58C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_173689.7(CRB2):​c.58C>T​(p.Leu20Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,395,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CRB2 NM_173689.7 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.376
• 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: Genomics England PanelApp, Orphanet, 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP7: Synonymous conserved (PhyloP=0.376 with no splicing effect.

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.58C>T	p.Leu20Leu	synonymous	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.58C>T	p.Leu20Leu	synonymous	Exon 1 of 13	ENSP00000362734.3	Q5IJ48-1
	CRB2	ENST00000896215.1		c.58C>T	p.Leu20Leu	synonymous	Exon 1 of 13	ENSP00000566274.1
	CRB2	ENST00000359999.7	TSL:2	c.58C>T	p.Leu20Leu	synonymous	Exon 1 of 10	ENSP00000353092.3	Q5IJ48-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1395520 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 688370

African (AFR) AF: 0.00 AC: 0 AN: 31536

American (AMR) AF: 0.00 AC: 0 AN: 35476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25116

East Asian (EAS) AF: 0.00 AC: 0 AN: 35608

South Asian (SAS) AF: 0.00 AC: 0 AN: 78958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078138

Other (OTH) AF: 0.0000173 AC: 1 AN: 57876

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.9
DANN	Benign	0.74
PhyloP100		0.38
PromoterAI		-0.044	Neutral

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: rs992216922; hg19: chr9-126118597;