rs12551047

Variant names:

• chr9-123356321-C-T
• rs12551047
• NM_173689.7:c.61C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_173689.7(CRB2):​c.61C>T​(p.Leu21Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,546,578 control chromosomes in the GnomAD database, including 2,796 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (469 hom., cov: 31)
  • Exomes 𝑓: 0.026 (2327 hom.)
• Consequence: CRB2 NM_173689.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.84
• Publications: 8 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 9-123356321-C-T is Benign according to our data. Variant chr9-123356321-C-T is described in ClinVar as Benign. ClinVar VariationId is 1166112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.84 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

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.61C>T	p.Leu21Leu	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.61C>T	p.Leu21Leu	synonymous	Exon 1 of 13	ENSP00000362734.3	Q5IJ48-1
	CRB2	ENST00000896215.1		c.61C>T	p.Leu21Leu	synonymous	Exon 1 of 13	ENSP00000566274.1
	CRB2	ENST00000359999.7	TSL:2	c.61C>T	p.Leu21Leu	synonymous	Exon 1 of 10	ENSP00000353092.3	Q5IJ48-2

Frequencies

GnomAD3 genomes AF: 0.0565 AC: 8597 AN: 152096 Hom.: 470 Cov.: 31

Gnomad AFR AF: 0.0984

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0467

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0425

GnomAD2 exomes AF: 0.0707 AC: 10658 AN: 150648 AF XY: 0.0674

Gnomad AFR exome AF: 0.0938

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.146

Gnomad FIN exome AF: 0.0487

Gnomad NFE exome AF: 0.00786

Gnomad OTH exome AF: 0.0509

GnomAD4 exome AF: 0.0257 AC: 35887 AN: 1394366 Hom.: 2327 Cov.: 32 AF XY: 0.0276 AC XY: 18987 AN XY: 687740

African (AFR) AF: 0.102 AC: 3208 AN: 31464

American (AMR) AF: 0.173 AC: 6061 AN: 34976

Ashkenazi Jewish (ASJ) AF: 0.00876 AC: 220 AN: 25116

East Asian (EAS) AF: 0.188 AC: 6690 AN: 35536

South Asian (SAS) AF: 0.111 AC: 8766 AN: 78696

European-Finnish (FIN) AF: 0.0479 AC: 2254 AN: 47096

Middle Eastern (MID) AF: 0.0249 AC: 141 AN: 5666

European-Non Finnish (NFE) AF: 0.00591 AC: 6369 AN: 1078008

Other (OTH) AF: 0.0377 AC: 2178 AN: 57808

GnomAD4 genome AF: 0.0565 AC: 8607 AN: 152212 Hom.: 469 Cov.: 31 AF XY: 0.0614 AC XY: 4568 AN XY: 74426

African (AFR) AF: 0.0983 AC: 4083 AN: 41522

American (AMR) AF: 0.113 AC: 1726 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.164 AC: 844 AN: 5150

South Asian (SAS) AF: 0.131 AC: 633 AN: 4822

European-Finnish (FIN) AF: 0.0467 AC: 496 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 684 AN: 67998

Other (OTH) AF: 0.0430 AC: 91 AN: 2114

Alfa AF: 0.0286 Hom.: 260

Bravo AF: 0.0650

Asia WGS AF: 0.175 AC: 605 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.7
DANN	Benign	0.72
PhyloP100		1.8
PromoterAI		-0.065	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12551047; hg19: chr9-126118600; COSMIC: COSV63503445;