9-123356265-C-T

Position:

chr9-123356265-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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 -16 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].

BS2

High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRB2	NM_173689.7 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/13	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.5C>T	p.Ala2Val	missense_variant	1/13	1	NM_173689.7	ENSP00000362734	P1	Q5IJ48-1
CRB2	ENST00000359999.7 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/10	2		ENSP00000353092		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

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CRB2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 14, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

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

MutationTaster

Benign

1.0

N;N

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