rs41302107

Variant names:

• chr1-197477907-T-C
• rs41302107
• ENST00000484075.5:n.*360T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000484075.5(CRB1):​n.*360T>C variant causes a non coding transcript exon 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 ENST00000484075.5 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.751
• Publications: 11 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: 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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 263259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CRB1	NM_201253.3	c.*28T>C		3_prime_UTR_variant	Exon 12 of 12	ENST00000367400.8	NP_957705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRB1	ENST00000367400.8	c.*28T>C		3_prime_UTR_variant	Exon 12 of 12	1	NM_201253.3	ENSP00000356370.3

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

GnomAD2 exomes AF: 0.0615 AC: 15346 AN: 249706 AF XY: 0.0611

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 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

African (AFR) AF: 0.0382 AC: 1268 AN: 33180

American (AMR) AF: 0.0430 AC: 1922 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.0446 AC: 1160 AN: 26024

East Asian (EAS) AF: 0.000404 AC: 16 AN: 39614

South Asian (SAS) AF: 0.0193 AC: 1654 AN: 85920

European-Finnish (FIN) AF: 0.0626 AC: 3337 AN: 53348

Middle Eastern (MID) AF: 0.0305 AC: 175 AN: 5734

European-Non Finnish (NFE) AF: 0.102 AC: 111667 AN: 1099718

Other (OTH) AF: 0.0705 AC: 4220 AN: 59860

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

African (AFR) AF: 0.0401 AC: 1665 AN: 41540

American (AMR) AF: 0.0566 AC: 864 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0438 AC: 152 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5168

South Asian (SAS) AF: 0.0192 AC: 92 AN: 4804

European-Finnish (FIN) AF: 0.0649 AC: 688 AN: 10606

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0959 AC: 6523 AN: 67990

Other (OTH) AF: 0.0616 AC: 130 AN: 2112

Alfa AF: 0.0782 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

Leber congenital amaurosis 8 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28819299) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Pigmented paravenous retinochoroidal atrophy Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 12 Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.75
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: rs41302107; hg19: chr1-197447037; COSMIC: COSV107470152; COSMIC: COSV107470152;