Variant 9-123370935-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The ENST00000373631.8(CRB2):c.1882C>T(p.Arg628Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,458,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R628H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CRB2
ENST00000373631.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 0.753

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a disulfide_bond (size 15) in uniprot entity CRUM2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in ENST00000373631.8

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

PP5

Variant 9-123370935-C-T is Pathogenic according to our data. Variant chr9-123370935-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180700.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-123370935-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRB2	NM_173689.7 linkuse as main transcript	c.1882C>T	p.Arg628Cys	missense_variant	7/13	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.1882C>T	p.Arg628Cys	missense_variant	7/13	1	NM_173689.7	ENSP00000362734	P1	Q5IJ48-1
CRB2	ENST00000359999.7 linkuse as main transcript	c.1882C>T	p.Arg628Cys	missense_variant	7/10	2		ENSP00000353092		Q5IJ48-2
CRB2	ENST00000460253.1 linkuse as main transcript	c.886C>T	p.Arg296Cys	missense_variant, NMD_transcript_variant	2/9	2		ENSP00000435279		Q5IJ48-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

247858

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134202

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000657

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000823

AC:

AN:

1458710

Hom.:

Cov.:

AF XY:

0.00000965

AC XY:

AN XY:

725214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000721

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Steroid-resistant nephrotic syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Focal segmental glomerulosclerosis 9

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 08, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

.;D

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.84

T;T

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.050

MutationAssessor

Pathogenic

3.1

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-4.3

D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.027

D;D

Sift4G

Uncertain

0.0050

D;T

Polyphen

1.0

D;D

Vest4

0.77

MVP

0.96

MPC

0.86

ClinPred

0.86

GERP RS

5.0

Varity_R

0.54

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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