NM_173689.7:c.5C>T

Variant names:

• chr9-123356265-C-T
• rs201425854
• NM_173689.7:c.5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173689.7(CRB2):​c.5C>T​(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,520,152 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0034 (21 hom.)
• Consequence: CRB2 NM_173689.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.552
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011595577).
• BP6: Variant 9-123356265-C-T is Benign according to our data. Variant chr9-123356265-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 729496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00313 (476/152254) while in subpopulation NFE AF = 0.00434 (295/67986). AF 95% confidence interval is 0.00393. There are 1 homozygotes in GnomAd4. There are 230 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 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.5C>T	p.Ala2Val	missense	Exon 1 of 13	NP_775960.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB2	ENST00000373631.8	TSL:1 MANE Select	c.5C>T	p.Ala2Val	missense	Exon 1 of 13	ENSP00000362734.3	Q5IJ48-1
	CRB2	ENST00000896215.1		c.5C>T	p.Ala2Val	missense	Exon 1 of 13	ENSP00000566274.1
	CRB2	ENST00000359999.7	TSL:2	c.5C>T	p.Ala2Val	missense	Exon 1 of 10	ENSP00000353092.3	Q5IJ48-2

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 476 AN: 152136 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00434

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00295 AC: 368 AN: 124704 AF XY: 0.00305

Gnomad AFR exome AF: 0.000789

Gnomad AMR exome AF: 0.000996

Gnomad ASJ exome AF: 0.000140

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.00371

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00335 AC: 4588 AN: 1367898 Hom.: 21 Cov.: 32 AF XY: 0.00335 AC XY: 2259 AN XY: 674654

African (AFR) AF: 0.000467 AC: 14 AN: 29968

American (AMR) AF: 0.000942 AC: 28 AN: 29734

Ashkenazi Jewish (ASJ) AF: 0.0000415 AC: 1 AN: 24070

East Asian (EAS) AF: 0.00 AC: 0 AN: 34980

South Asian (SAS) AF: 0.00186 AC: 143 AN: 76948

European-Finnish (FIN) AF: 0.0108 AC: 446 AN: 41326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5234

European-Non Finnish (NFE) AF: 0.00358 AC: 3829 AN: 1069090

Other (OTH) AF: 0.00225 AC: 127 AN: 56548

GnomAD4 genome AF: 0.00313 AC: 476 AN: 152254 Hom.: 1 Cov.: 31 AF XY: 0.00309 AC XY: 230 AN XY: 74448

African (AFR) AF: 0.000650 AC: 27 AN: 41540

American (AMR) AF: 0.00222 AC: 34 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00434 AC: 295 AN: 67986

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00282 Hom.: 0

Bravo AF: 0.00212

ESP6500AA AF: 0.000285 AC: 1

ESP6500EA AF: 0.00148 AC: 10

ExAC AF: 0.00117 AC: 59

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	CRB2-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Benign	0.061
Eigen_PC	Benign	0.085
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.55
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.15
MVP		0.89
MPC		0.27
ClinPred		0.033	T
GERP RS		3.2
PromoterAI		-0.16	Neutral
Varity_R		0.23
gMVP		0.52
Mutation Taster		=93/7	polymorphism

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: rs201425854; hg19: chr9-126118544; COSMIC: COSV63501486;