9-123376950-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_173689.7(CRB2):c.3746G>A(p.Arg1249Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000724 in 1,606,200 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00088 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00071 ( 10 hom. )

Consequence

CRB2
NM_173689.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:2

Conservation

PhyloP100: 5.57

Publications

9 publications found

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 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: G2P, Genomics England PanelApp, Orphanet
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AR Classification: LIMITED Submitted by: G2P

CRB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012366444).

BP6

Variant 9-123376950-G-A is Benign according to our data. Variant chr9-123376950-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180703.

BS2

High Homozygotes in GnomAdExome4 at 10 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB2	NM_173689.7	MANE Select	c.3746G>A	p.Arg1249Gln	missense	Exon 13 of 13	NP_775960.4
	CRB2	NR_104603.2		n.2860G>A		non_coding_transcript_exon	Exon 8 of 9

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB2	ENST00000373631.8	TSL:1 MANE Select	c.3746G>A	p.Arg1249Gln	missense	Exon 13 of 13	ENSP00000362734.3
	CRB2	ENST00000460253.1	TSL:2	n.2750G>A		non_coding_transcript_exon	Exon 8 of 9	ENSP00000435279.1

Frequencies

GnomAD3 genomes

AF:

0.000881

AC:

134

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00138

AC:

319

AN:

231990

AF XY:

0.00132

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000579

Gnomad ASJ exome

AF:

0.0247

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000481

Gnomad OTH exome

AF:

0.00211

GnomAD4 exome

AF:

0.000708

AC:

1029

AN:

1454030

Hom.:

Cov.:

AF XY:

0.000709

AC XY:

512

AN XY:

722586

show subpopulations

African (AFR)

AF:

0.0000898

AC:

AN:

33422

American (AMR)

AF:

0.000505

AC:

AN:

43598

Ashkenazi Jewish (ASJ)

AF:

0.0255

AC:

661

AN:

25930

East Asian (EAS)

AF:

0.00

AC:

AN:

39452

South Asian (SAS)

AF:

0.0000472

AC:

AN:

84782

European-Finnish (FIN)

AF:

0.0000194

AC:

AN:

51640

Middle Eastern (MID)

AF:

0.000179

AC:

AN:

5576

European-Non Finnish (NFE)

AF:

0.000196

AC:

218

AN:

1109550

Other (OTH)

AF:

0.00198

AC:

119

AN:

60080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000881

AC:

134

AN:

152170

Hom.:

Cov.:

AF XY:

0.000928

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.000327

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0291

AC:

101

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000367

AC:

AN:

68030

Other (OTH)

AF:

0.00144

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00128

Hom.:

Bravo

AF:

0.00102

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00104

AC:

126

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Focal segmental glomerulosclerosis 9

Pathogenic:1Uncertain:1

Jan 08, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

NM_173689.5:c.3746G>A in the CRB2 gene has an allele frequency of 0.025 in Ashkenazi Jewish subpopulation in the gnomAD database. 4 homozygous occurrences are observed in the gnomAD database. Ebarasi et al. reported a homozygozity in a patient with Steroid-Resistant Nephrotic Syndrome in a consanguineous family (PMID: 25557779). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BS1.

not provided

Benign:2

Mar 09, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria.

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Uncertain:1

Dec 07, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3746G>A (p.R1249Q) alteration is located in exon 13 (coding exon 13) of the CRB2 gene. This alteration results from a G to A substitution at nucleotide position 3746, causing the arginine (R) at amino acid position 1249 to be replaced by a glutamine (Q). The in silico prediction for the p.R1249Q alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.010

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.012

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.6

PhyloP100

5.6

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.87

Sift

Uncertain

0.011

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.73

MVP

0.97

MPC

0.22

ClinPred

0.45

GERP RS

5.4

Varity_R

0.22

gMVP

0.55

Mutation Taster

=31/69

disease causing

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over