1-197344059-C-T

Variant names:

• chr1-197344059-C-T
• rs949571
• NM_201253.3:c.653-222C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_201253.3(CRB1):​c.653-222C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 152,190 control chromosomes in the GnomAD database, including 27,512 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (27512 hom., cov: 33)
• Consequence: CRB1 NM_201253.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.373
• Publications: 13 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

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.653-222C>T		intron	N/A	NP_957705.1	P82279-1
	CRB1	NM_001257965.2		c.446-222C>T		intron	N/A	NP_001244894.1	F5H0L2
	CRB1	NM_001193640.2		c.653-12772C>T		intron	N/A	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.653-222C>T		intron	N/A	ENSP00000356370.3	P82279-1
	CRB1	ENST00000638467.1	TSL:1	c.653-222C>T		intron	N/A	ENSP00000491102.1	P82279-2
	CRB1	ENST00000367399.6	TSL:1	c.653-12772C>T		intron	N/A	ENSP00000356369.2	P82279-3

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84972 AN: 152072 Hom.: 27514 Cov.: 33

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.695

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.807

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.679

Gnomad OTH AF: 0.615

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

GnomAD4 genome AF: 0.558 AC: 84988 AN: 152190 Hom.: 27512 Cov.: 33 AF XY: 0.570 AC XY: 42397 AN XY: 74394

African (AFR) AF: 0.205 AC: 8527 AN: 41522

American (AMR) AF: 0.676 AC: 10336 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 2413 AN: 3472

East Asian (EAS) AF: 0.749 AC: 3875 AN: 5176

South Asian (SAS) AF: 0.807 AC: 3891 AN: 4824

European-Finnish (FIN) AF: 0.739 AC: 7817 AN: 10582

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.679 AC: 46208 AN: 68008

Other (OTH) AF: 0.614 AC: 1298 AN: 2114

Alfa AF: 0.647 Hom.: 143714

Bravo AF: 0.535

Asia WGS AF: 0.731 AC: 2540 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Benign	0.49
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

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: rs949571; hg19: chr1-197313189; COSMIC: COSV66338095;