NM_173689.7:c.94+184G>A

Variant names:

• chr9-123356538-G-A
• rs79961016
• NM_173689.7:c.94+184G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_173689.7(CRB2):​c.94+184G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0082 in 148,658 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0082 (20 hom., cov: 29)
• Consequence: CRB2 NM_173689.7 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.338
• 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: Orphanet, Genomics England PanelApp, G2P
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 9-123356538-G-A is Benign according to our data. Variant chr9-123356538-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1212825.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0082 (1219/148658) while in subpopulation AFR AF = 0.0288 (1157/40188). AF 95% confidence interval is 0.0274. There are 20 homozygotes in GnomAd4. There are 591 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB2	NM_173689.7	MANE Select	c.94+184G>A		intron	N/A	NP_775960.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB2	ENST00000373631.8	TSL:1 MANE Select	c.94+184G>A		intron	N/A	ENSP00000362734.3	Q5IJ48-1
	CRB2	ENST00000896215.1		c.94+184G>A		intron	N/A	ENSP00000566274.1
	CRB2	ENST00000359999.7	TSL:2	c.94+184G>A		intron	N/A	ENSP00000353092.3	Q5IJ48-2

Frequencies

GnomAD3 genomes AF: 0.00806 AC: 1197 AN: 148550 Hom.: 17 Cov.: 29

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00225

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000426

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.000237

Gnomad OTH AF: 0.00441

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00820 AC: 1219 AN: 148658 Hom.: 20 Cov.: 29 AF XY: 0.00818 AC XY: 591 AN XY: 72272

African (AFR) AF: 0.0288 AC: 1157 AN: 40188

American (AMR) AF: 0.00225 AC: 33 AN: 14690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 4970

South Asian (SAS) AF: 0.000426 AC: 2 AN: 4690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9918

Middle Eastern (MID) AF: 0.00699 AC: 2 AN: 286

European-Non Finnish (NFE) AF: 0.000237 AC: 16 AN: 67480

Other (OTH) AF: 0.00437 AC: 9 AN: 2060

Alfa AF: 0.00613 Hom.: 1

Bravo AF: 0.00865

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.2
DANN	Benign	0.84
PhyloP100		0.34
PromoterAI		0.016	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs79961016; hg19: chr9-126118817;