9-123371542-C-G

Position:

chr9-123371542-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5

The NM_173689.7(CRB2):c.2400C>G(p.Asn800Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,613,014 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

CRB2
NM_173689.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 0.0250

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity CRUM2_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-123371542-C-G is Pathogenic according to our data. Variant chr9-123371542-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 546072.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}. Variant chr9-123371542-C-G 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.2400C>G	p.Asn800Lys	missense_variant	8/13	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.2400C>G	p.Asn800Lys	missense_variant	8/13	1	NM_173689.7	ENSP00000362734.3	Q5IJ48-1
CRB2	ENST00000359999.7 linkuse as main transcript	c.2400C>G	p.Asn800Lys	missense_variant	8/10	2		ENSP00000353092.3	Q5IJ48-2
CRB2	ENST00000460253.1 linkuse as main transcript	n.1404C>G		non_coding_transcript_exon_variant	3/9	2		ENSP00000435279.1	Q5IJ48-3

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000233

AC:

AN:

249184

Hom.:

AF XY:

0.000222

AC XY:

AN XY:

135232

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00540

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000121

AC:

177

AN:

1460792

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

726716

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00482

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000105

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000495

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ventriculomegaly-cystic kidney disease

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 08, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 05, 2022	This sequence change is predicted to replace asparagine with lysine at codon 800 of the CRB2 protein, p.(Asn800Lys). The asparagine residue is highly conserved (100 vertebrates, UCSC), and is a glycosylation site N-linked (GlcNAc) asparagine in the laminin G-like 2 domain. There is a moderate physicochemical difference between asparagine and lysine. The variant is present in a large population cohort at a frequency of 0.02% (58/249,184 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.5% in the Ashkenazi Jewish sub-population. It has been identified with a second allele in at least five individuals with either or both ventriculomegaly (most common feature) and renal anomalies, and segregates with disease in multiple families (PMID: 25557780, 26925547, 27004616, 30996265). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PP1_Strong, PM2_Supporting, PP3. -
Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_173689.5:c.2400C>G in the CRB2 gene has an allele frequency of 0.005 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been detected in two siblings of a family affected with cerebral ventriculomegaly and renal microcysts, in trans with mutation c.2277G>A (p.Trp759Ter) and in another family in trans with mutation c.1928A>C (p.Glu643Ala) (PMID: 25557780). In-silico tools predict a damaging effect of the variant on protein function. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong; PP1; PP3. -

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30212996, 30586318, 27004616, 28425981, 25557780, 27867342, 26925547, 33969091, 30996265, 33687977) -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 800 of the CRB2 protein (p.Asn800Lys). This variant is present in population databases (rs765676223, gnomAD 0.5%). This missense change has been observed in individual(s) with clinical features of CRB2-related conditions (PMID: 25557780, 26925547, 27004616, 30586318). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 546072). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CRB2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CRB2 function (PMID: 36549870). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

.;T

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.73

T;T

M_CAP

Pathogenic

0.30

MetaRNN

Uncertain

0.48

T;T

MetaSVM

Uncertain

-0.064

MutationAssessor

Pathogenic

3.4

M;M

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0050

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.83

MutPred

0.45

Gain of methylation at N800 (P = 0.0115);Gain of methylation at N800 (P = 0.0115);

MVP

0.92

MPC

0.55

ClinPred

0.47

GERP RS

4.8

Varity_R

0.53

gMVP

0.75

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