rs147412276

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

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

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRB2	NM_173689.7 linkuse as main transcript	c.3746G>A	p.Arg1249Gln	missense_variant	13/13	ENST00000373631.8	NP_775960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRB2	ENST00000373631.8 linkuse as main transcript	c.3746G>A	p.Arg1249Gln	missense_variant	13/13	1	NM_173689.7	ENSP00000362734	P1	Q5IJ48-1
CRB2	ENST00000460253.1 linkuse as main transcript	c.2750G>A	p.Arg917Gln	missense_variant, NMD_transcript_variant	8/9	2		ENSP00000435279		Q5IJ48-3

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

GnomAD3 exomes

AF:

0.00138

AC:

319

AN:

231990

Hom.:

AF XY:

0.00132

AC XY:

166

AN XY:

126206

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 SAS exome

AF:

0.0000697

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

Gnomad4 AFR exome

AF:

0.0000898

Gnomad4 AMR exome

AF:

0.000505

Gnomad4 ASJ exome

AF:

0.0255

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000472

Gnomad4 FIN exome

AF:

0.0000194

Gnomad4 NFE exome

AF:

0.000196

Gnomad4 OTH exome

AF:

0.00198

GnomAD4 genome

AF:

0.000881

AC:

134

AN:

152170

Hom.:

Cov.:

AF XY:

0.000928

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.0291

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000367

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.00146

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 08, 2015	- -
Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2020	See Variant Classification Assertion Criteria. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2020

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.010

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

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

MutationTaster

Benign

1.0

D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over