rs281865175

Variant names:

• chr1-197477774-AAGGGCAACTC-A
• rs281865175
• NM_201253.3:c.4121_4130delCAACTCAGGG

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.87
• Publications: 1 publications found

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

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB1	NM_201253.3	MANE Select	c.4121_4130delCAACTCAGGG	p.Ala1374GlufsTer20	frameshift	Exon 12 of 12	NP_957705.1	P82279-1
	CRB1	NM_001257965.2		c.4049_4058delCAACTCAGGG	p.Ala1350GlufsTer20	frameshift	Exon 15 of 15	NP_001244894.1	F5H0L2
	CRB1	NM_001193640.2		c.3785_3794delCAACTCAGGG	p.Ala1262GlufsTer20	frameshift	Exon 10 of 10	NP_001180569.1	P82279-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB1	ENST00000367400.8	TSL:1 MANE Select	c.4121_4130delCAACTCAGGG	p.Ala1374GlufsTer20	frameshift	Exon 12 of 12	ENSP00000356370.3	P82279-1
	CRB1	ENST00000367399.6	TSL:1	c.3785_3794delCAACTCAGGG	p.Ala1262GlufsTer20	frameshift	Exon 10 of 10	ENSP00000356369.2	P82279-3
	CRB1	ENST00000448952.1	TSL:1	c.*226_*235delCAACTCAGGG		3_prime_UTR	Exon 2 of 2	ENSP00000395407.1	A0A0C4DG35

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Leber congenital amaurosis 8 (3)
2	-	-	Retinitis pigmentosa 12 (2)
1	-	-	Leber congenital amaurosis (1)
1	-	-	not provided (2)
1	-	-	Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs281865175; hg19: chr1-197446904;