dbSNP rs398124615: CRB1:p.Ile167_Gly169del (chr1-197328843-GGATGGAATT-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PM1PM4PP5BS1_SupportingBS2

The NM_201253.3(CRB1):c.498_506delAATTGATGG(p.Ile167_Gly169del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00123 in 1,614,162 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 7 hom. )

Consequence

CRB1
NM_201253.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:21U:2B:1

Conservation

PhyloP100: 3.87

Publications

7 publications found

Variant links:

Genes affected

CRB1 (HGNC:2343): (crumbs cell polarity complex component 1) This gene encodes a protein which is similar to the Drosophila crumbs protein and localizes to the inner segment of mammalian photoreceptors. In Drosophila crumbs localizes to the stalk of the fly photoreceptor and may be a component of the molecular scaffold that controls proper development of polarity in the eye. Mutations in this gene are associated with a severe form of retinitis pigmentosa, RP12, and with Leber congenital amaurosis. Alternate splicing results in multiple transcript variants, some protein coding and some non-protein coding.[provided by RefSeq, Apr 2012]

CRB1 Gene-Disease associations (from GenCC):

hereditary macular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
Leber congenital amaurosis 8
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
retinitis pigmentosa 12
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
nanophthalmia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pigmented paravenous retinochoroidal atrophy
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CRB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_201253.3

PM4

Nonframeshift variant in NON repetitive region in NM_201253.3.

PP5

Variant 1-197328843-GGATGGAATT-G is Pathogenic according to our data. Variant chr1-197328843-GGATGGAATT-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96659.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000775 (118/152348) while in subpopulation NFE AF = 0.00132 (90/68034). AF 95% confidence interval is 0.0011. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201253.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRB1	NM_201253.3	MANE Select	c.498_506delAATTGATGG	p.Ile167_Gly169del	disruptive_inframe_deletion	Exon 2 of 12	NP_957705.1	P82279-1
CRB1	NM_001257965.2		c.291_299delAATTGATGG	p.Ile98_Gly100del	disruptive_inframe_deletion	Exon 4 of 15	NP_001244894.1	F5H0L2
CRB1	NM_001193640.2		c.498_506delAATTGATGG	p.Ile167_Gly169del	disruptive_inframe_deletion	Exon 2 of 10	NP_001180569.1	P82279-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRB1	ENST00000367400.8	TSL:1 MANE Select	c.498_506delAATTGATGG	p.Ile167_Gly169del	disruptive_inframe_deletion	Exon 2 of 12	ENSP00000356370.3	P82279-1
CRB1	ENST00000638467.1	TSL:1	c.498_506delAATTGATGG	p.Ile167_Gly169del	disruptive_inframe_deletion	Exon 2 of 11	ENSP00000491102.1	P82279-2
CRB1	ENST00000367399.6	TSL:1	c.498_506delAATTGATGG	p.Ile167_Gly169del	disruptive_inframe_deletion	Exon 2 of 10	ENSP00000356369.2	P82279-3

Frequencies

GnomAD3 genomes

AF:

0.000775

AC:

118

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000625

AC:

157

AN:

251256

AF XY:

0.000589

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000724

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000968

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00127

AC:

1863

AN:

1461814

Hom.:

AF XY:

0.00122

AC XY:

886

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33476

American (AMR)

AF:

0.000671

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.000689

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00158

AC:

1754

AN:

1111968

Other (OTH)

AF:

0.000844

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

111

222

333

444

555

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000775

AC:

118

AN:

152348

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41592

American (AMR)

AF:

0.000915

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00132

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000249

Hom.:

Bravo

AF:

0.000903

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.00154

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Macular dystrophy (3)

CRB1-related disorder (2)

Leber congenital amaurosis 8 (2)

Retinal dystrophy (2)

Retinitis pigmentosa 12 (2)

Autosomal recessive bestrophinopathy (1)

Cone dystrophy (1)

CRB1-related maculopathy (1)

Leber congenital amaurosis 1 (1)

not specified (1)

Retinitis pigmentosa 12;C1868310:Pigmented paravenous retinochoroidal atrophy;C3151202:Leber congenital amaurosis 8 (1)

Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.9

Mutation Taster

=99/101

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over