Variant rs730880377 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_173689.7(CRB2):c.1897C>G(p.Arg633Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,457,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R633W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CRB2
NM_173689.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.747

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:

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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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-123370950-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 180707.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRB2	NM_173689.7 linkuse as main transcript	c.1897C>G	p.Arg633Gly	missense_variant	7/13	ENST00000373631.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRB2	ENST00000373631.8 linkuse as main transcript	c.1897C>G	p.Arg633Gly	missense_variant	7/13	1	NM_173689.7	P1	Q5IJ48-1
CRB2	ENST00000359999.7 linkuse as main transcript	c.1897C>G	p.Arg633Gly	missense_variant	7/10	2			Q5IJ48-2
CRB2	ENST00000460253.1 linkuse as main transcript	c.901C>G	p.Arg301Gly	missense_variant, NMD_transcript_variant	2/9	2			Q5IJ48-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000405

AC:

AN:

246706

Hom.:

AF XY:

0.00000749

AC XY:

AN XY:

133536

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000905

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1457580

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724350

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000631

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000313

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.65

.;D

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.76

T;T

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

0.078

MutationAssessor

Benign

1.6

L;L

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-6.7

D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

1.0

D;D

Vest4

0.79

MutPred

0.61

Loss of stability (P = 0.1568);Loss of stability (P = 0.1568);

MVP

0.86

MPC

0.50

ClinPred

0.57

GERP RS

1.6

Varity_R

0.40

gMVP

0.86

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over