Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_201253.3(CRB1):c.99G>T(p.Arg33Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,613,906 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R33G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0060 ( 7 hom., cov: 33)

Exomes 𝑓: 0.00060 ( 13 hom. )

Consequence

CRB1
NM_201253.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3O:1

Conservation

PhyloP100: 0.175

Publications

3 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: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
retinitis pigmentosa 12
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
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: G2P, Orphanet
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: Benign. The variant received -10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_201253.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 168 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: -1.2832 (below the threshold of 3.09). Trascript score misZ: 0.62189 (below the threshold of 3.09). GenCC associations: The gene is linked to Leber congenital amaurosis 8, retinitis pigmentosa 12, pigmented paravenous retinochoroidal atrophy, hereditary macular dystrophy, retinitis pigmentosa, Leber congenital amaurosis, nanophthalmia.

BP4

Computational evidence support a benign effect (MetaRNN=0.007971734).

BP6

Variant 1-197328450-G-T is Benign according to our data. Variant chr1-197328450-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 100609.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00599 (911/152200) while in subpopulation AFR AF = 0.0205 (851/41528). AF 95% confidence interval is 0.0193. There are 7 homozygotes in GnomAd4. There are 441 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 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
CRB1	NM_201253.3	MANE Select	c.99G>T	p.Arg33Ser	missense	Exon 2 of 12	NP_957705.1
CRB1	NM_001257965.2		c.-109G>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 15	NP_001244894.1
CRB1	NM_001193640.2		c.99G>T	p.Arg33Ser	missense	Exon 2 of 10	NP_001180569.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CRB1	ENST00000367400.8	TSL:1 MANE Select	c.99G>T	p.Arg33Ser	missense	Exon 2 of 12	ENSP00000356370.3
CRB1	ENST00000638467.1	TSL:1	c.99G>T	p.Arg33Ser	missense	Exon 2 of 11	ENSP00000491102.1
CRB1	ENST00000367399.6	TSL:1	c.99G>T	p.Arg33Ser	missense	Exon 2 of 10	ENSP00000356369.2

Frequencies

GnomAD3 genomes

AF:

0.00599

AC:

911

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0206

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00141

AC:

354

AN:

250996

AF XY:

0.00108

show subpopulations

Gnomad AFR exome

AF:

0.0207

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000819

GnomAD4 exome

AF:

0.000602

AC:

880

AN:

1461706

Hom.:

Cov.:

AF XY:

0.000494

AC XY:

359

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.0220

AC:

735

AN:

33474

American (AMR)

AF:

0.000648

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

1111850

Other (OTH)

AF:

0.00106

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00599

AC:

911

AN:

152200

Hom.:

Cov.:

AF XY:

0.00593

AC XY:

441

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0205

AC:

851

AN:

41528

American (AMR)

AF:

0.00242

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68026

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

128

171

214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00261

Hom.:

Bravo

AF:

0.00655

ESP6500AA

AF:

0.0191

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00175

AC:

213

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leber congenital amaurosis 8 (1)

not provided (2)

Pigmented paravenous retinochoroidal atrophy (1)

Retinitis pigmentosa (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.21

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0080

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.7

PhyloP100

0.17

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.9

REVEL

Benign

0.21

Sift

Benign

0.55

Sift4G

Benign

0.069

Polyphen

0.10

Vest4

0.35

MutPred

0.41

Gain of disorder (P = 0.061)

MVP

0.90

MPC

0.041

ClinPred

0.0076

GERP RS

-0.51

Varity_R

0.13

gMVP

0.78

Mutation Taster

=89/11

polymorphism

(source)

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

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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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over