rs879255252

Variant names:

• chr9-123370939-G-A
• rs879255252
• NM_173689.7:c.1886G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-123370939-G-A
• chr9-123370939-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM5 PP3_Strong

The NM_173689.7(CRB2):​c.1886G>A​(p.Cys629Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000117 in 1,457,794 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. C629S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CRB2 NM_173689.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.80
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• ventriculomegaly-cystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Orphanet
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-123370939-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 180702.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.997

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173689.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB2	NM_173689.7	MANE Select	c.1886G>A	p.Cys629Tyr	missense	Exon 7 of 13	NP_775960.4
	CRB2	NR_104603.2		n.1000G>A		non_coding_transcript_exon	Exon 2 of 9

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB2	ENST00000373631.8	TSL:1 MANE Select	c.1886G>A	p.Cys629Tyr	missense	Exon 7 of 13	ENSP00000362734.3
	CRB2	ENST00000359999.7	TSL:2	c.1886G>A	p.Cys629Tyr	missense	Exon 7 of 10	ENSP00000353092.3
	CRB2	ENST00000460253.1	TSL:2	n.890G>A		non_coding_transcript_exon	Exon 2 of 9	ENSP00000435279.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1457794 Hom.: 0 Cov.: 54 AF XY: 0.00000690 AC XY: 5 AN XY: 724594

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 85910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1109490

Other (OTH) AF: 0.0000166 AC: 1 AN: 60210

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		6.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.99		Loss of disorder (P = 0.0706)
MVP		1.0
MPC		0.73
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
gMVP		0.98
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs879255252; hg19: chr9-126133218;