rs41302107

Positions:

• chr1-197477907-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201253.3(CRB1):​c.*28T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0848 in 1,600,232 control chromosomes in the GnomAD database, including 6,713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (467 hom., cov: 32)
  • Exomes 𝑓: 0.087 (6246 hom.)
• Consequence: CRB1 NM_201253.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.751

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-197477907-T-C is Benign according to our data. Variant chr1-197477907-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 263259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197477907-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.094 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRB1	NM_201253.3	c.*28T>C		3_prime_UTR_variant	12/12	ENST00000367400.8	NP_957705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRB1	ENST00000367400.8	c.*28T>C		3_prime_UTR_variant	12/12	1	NM_201253.3	ENSP00000356370	P1

Frequencies

GnomAD3 genomes AF: 0.0680 AC: 10337 AN: 152052 Hom.: 467 Cov.: 32

Gnomad AFR AF: 0.0402

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.0566

Gnomad ASJ AF: 0.0438

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.0649

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0960

Gnomad OTH AF: 0.0622

GnomAD3 exomes AF: 0.0615 AC: 15346 AN: 249706 Hom.: 635 AF XY: 0.0611 AC XY: 8254 AN XY: 134980

Gnomad AFR exome AF: 0.0376

Gnomad AMR exome AF: 0.0399

Gnomad ASJ exome AF: 0.0425

Gnomad EAS exome AF: 0.00103

Gnomad SAS exome AF: 0.0179

Gnomad FIN exome AF: 0.0609

Gnomad NFE exome AF: 0.0949

Gnomad OTH exome AF: 0.0631

GnomAD4 exome AF: 0.0866 AC: 125419 AN: 1448062 Hom.: 6246 Cov.: 27 AF XY: 0.0835 AC XY: 60209 AN XY: 721216

Gnomad4 AFR exome AF: 0.0382

Gnomad4 AMR exome AF: 0.0430

Gnomad4 ASJ exome AF: 0.0446

Gnomad4 EAS exome AF: 0.000404

Gnomad4 SAS exome AF: 0.0193

Gnomad4 FIN exome AF: 0.0626

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.0705

GnomAD4 genome AF: 0.0679 AC: 10336 AN: 152170 Hom.: 467 Cov.: 32 AF XY: 0.0653 AC XY: 4858 AN XY: 74382

Gnomad4 AFR AF: 0.0401

Gnomad4 AMR AF: 0.0566

Gnomad4 ASJ AF: 0.0438

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0192

Gnomad4 FIN AF: 0.0649

Gnomad4 NFE AF: 0.0959

Gnomad4 OTH AF: 0.0616

Alfa AF: 0.0790 Hom.: 138

Bravo AF: 0.0675

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28819299) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Leber congenital amaurosis 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Pigmented paravenous retinochoroidal atrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

- -

Retinitis pigmentosa 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.59
DANN	Benign	0.58

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

LitVar

Other links and lift over

dbSNP: rs41302107; hg19: chr1-197447037;