NM_201253.3:c.4121_4130delCAACTCAGGG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_201253.3(CRB1):c.4121_4130delCAACTCAGGG(p.Ala1374GlufsTer20) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A1374A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CRB1
NM_201253.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.87

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 17 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-197477774-AAGGGCAACTC-A is Pathogenic according to our data. Variant chr1-197477774-AAGGGCAACTC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 5740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.4121_4130delCAACTCAGGG	p.Ala1374GlufsTer20	frameshift	Exon 12 of 12	NP_957705.1
CRB1	NM_001257965.2		c.4049_4058delCAACTCAGGG	p.Ala1350GlufsTer20	frameshift	Exon 15 of 15	NP_001244894.1
CRB1	NM_001193640.2		c.3785_3794delCAACTCAGGG	p.Ala1262GlufsTer20	frameshift	Exon 10 of 10	NP_001180569.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CRB1	ENST00000367400.8	TSL:1 MANE Select	c.4121_4130delCAACTCAGGG	p.Ala1374GlufsTer20	frameshift	Exon 12 of 12	ENSP00000356370.3
CRB1	ENST00000367399.6	TSL:1	c.3785_3794delCAACTCAGGG	p.Ala1262GlufsTer20	frameshift	Exon 10 of 10	ENSP00000356369.2
CRB1	ENST00000484075.5	TSL:1	n.232_241delCAACTCAGGG		non_coding_transcript_exon	Exon 12 of 12	ENSP00000433932.1

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis 8

Pathogenic:3

Laboratory of Genetics in Ophthalmology, Institut Imagine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 15, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Retinitis pigmentosa 12

Pathogenic:2

Feb 15, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:1Other:1

May 27, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Leber congenital amaurosis

Pathogenic:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8

Pathogenic:1

Mar 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ala1374Glufs*20) in the CRB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 33 amino acid(s) of the CRB1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with inherited retinal dystrophy (PMID: 12567265). It has also been observed to segregate with disease in related individuals. This variant is also known as del 4121‚Äö√Ñ√¨4130. ClinVar contains an entry for this variant (Variation ID: 5740). This variant disrupts a region of the CRB1 protein in which other variant(s) (p.Arg1390*) have been determined to be pathogenic (PMID: 23379534, 29068479). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.9

Mutation Taster

=1/199

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over