rs879255252

Positions:

• chr9-123370939-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_173689.7(CRB2):​c.1886G>C​(p.Cys629Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRB2 NM_173689.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.80

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.997
• PP5: Variant 9-123370939-G-C is Pathogenic according to our data. Variant chr9-123370939-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 180702.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-123370939-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRB2	NM_173689.7	c.1886G>C	p.Cys629Ser	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	c.1886G>C	p.Cys629Ser	missense_variant	7/13	1	NM_173689.7	ENSP00000362734.3
CRB2	ENST00000359999.7	c.1886G>C	p.Cys629Ser	missense_variant	7/10	2		ENSP00000353092.3
CRB2	ENST00000460253.1	n.890G>C		non_coding_transcript_exon_variant	2/9	2		ENSP00000435279.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 54

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	.;D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.71	T;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.4	H;H
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-9.9	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.99		Gain of disorder (P = 0.0333);Gain of disorder (P = 0.0333);
MVP		0.99
MPC		0.42
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
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

Other links and lift over

dbSNP: rs879255252; hg19: chr9-126133218;