9-123356265-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_173689.7(CRB2):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,520,152 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0034 ( 21 hom. )

Consequence

CRB2
NM_173689.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.552

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011595577).

BP6

Variant 9-123356265-C-T is Benign according to our data. Variant chr9-123356265-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 729496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-123356265-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00313 (476/152254) while in subpopulation NFE AF= 0.00434 (295/67986). AF 95% confidence interval is 0.00393. There are 1 homozygotes in gnomad4. There are 230 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRB2	NM_173689.7 link	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 13	ENST00000373631.8	NP_775960.4	Q5IJ48-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRB2	ENST00000373631.8 link	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 13	1	NM_173689.7	ENSP00000362734.3		Q5IJ48-1
CRB2	ENST00000359999.7 link	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 10	2		ENSP00000353092.3		Q5IJ48-2

Frequencies

GnomAD3 genomes

AF:

0.00313

AC:

476

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0106

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00434

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00295

AC:

368

AN:

124704

Hom.:

AF XY:

0.00305

AC XY:

208

AN XY:

68246

show subpopulations

Gnomad AFR exome

AF:

0.000789

Gnomad AMR exome

AF:

0.000996

Gnomad ASJ exome

AF:

0.000140

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00199

Gnomad FIN exome

AF:

0.0106

Gnomad NFE exome

AF:

0.00371

Gnomad OTH exome

AF:

0.00282

GnomAD4 exome

AF:

0.00335

AC:

4588

AN:

1367898

Hom.:

Cov.:

AF XY:

0.00335

AC XY:

2259

AN XY:

674654

show subpopulations

Gnomad4 AFR exome

AF:

0.000467

Gnomad4 AMR exome

AF:

0.000942

Gnomad4 ASJ exome

AF:

0.0000415

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00186

Gnomad4 FIN exome

AF:

0.0108

Gnomad4 NFE exome

AF:

0.00358

Gnomad4 OTH exome

AF:

0.00225

GnomAD4 genome

AF:

0.00313

AC:

476

AN:

152254

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

230

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0106

Gnomad4 NFE

AF:

0.00434

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00282

Hom.:

Bravo

AF:

0.00212

ESP6500AA

AF:

0.000285

AC:

ESP6500EA

AF:

0.00148

AC:

ExAC

AF:

0.00117

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

CRB2-related disorder

Benign:1

Jan 14, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Oct 18, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.040

.;T

Eigen

Benign

0.061

Eigen_PC

Benign

0.085

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.54

T;T

M_CAP

Pathogenic

0.86

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.1

L;L

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.28

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.99

D;D

Vest4

0.15

MVP

0.89

MPC

0.27

ClinPred

0.033

GERP RS

3.2

Varity_R

0.23

gMVP

0.52

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