Variant 9-123370912-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_173689.7(CRB2):c.1859G>C(p.Cys620Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,820 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CRB2
NM_173689.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 9.88

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:

CRB2 (HGNC:):

CRB2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRB2	NM_173689.7 linkuse as main transcript	c.1859G>C	p.Cys620Ser	missense_variant	7/13	ENST00000373631.8	NP_775960.4	Q5IJ48-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CRB2	ENST00000373631.8 linkuse as main transcript	c.1859G>C	p.Cys620Ser	missense_variant	7/13	1	NM_173689.7	ENSP00000362734.3	Q5IJ48-1
CRB2	ENST00000359999.7 linkuse as main transcript	c.1859G>C	p.Cys620Ser	missense_variant	7/10	2		ENSP00000353092.3	Q5IJ48-2
CRB2	ENST00000460253.1 linkuse as main transcript	n.863G>C		non_coding_transcript_exon_variant	2/9	2		ENSP00000435279.1	Q5IJ48-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460820

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726678

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Focal segmental glomerulosclerosis 9

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 08, 2015

- -

Ventriculomegaly-cystic kidney disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 02, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

.;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.71

T;T

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

1.0

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.7

H;H

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-9.9

D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.98

MutPred

0.98

Gain of disorder (P = 0.0412);Gain of disorder (P = 0.0412);

MVP

0.98

MPC

0.42

ClinPred

1.0

GERP RS

5.0

Varity_R

1.0

gMVP

0.97

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