1-197328410-A-T

Variant names:

• chr1-197328410-A-T
• rs12042179
• NM_201253.3:c.71-12A>T

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.71-12A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 1,590,246 control chromosomes in the GnomAD database, including 145,185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (11869 hom., cov: 32)
  • Exomes 𝑓: 0.42 (133316 hom.)
• Consequence: CRB1 NM_201253.3 intron
• Scores: Splicing: ADA: 0.00006066
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.190

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=-0.7).
• BP6: Variant 1-197328410-A-T is Benign according to our data. Variant chr1-197328410-A-T is described in ClinVar as [Benign]. Clinvar id is 96660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197328410-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRB1	NM_201253.3	c.71-12A>T		intron_variant	Intron 1 of 11	ENST00000367400.8	NP_957705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRB1	ENST00000367400.8	c.71-12A>T		intron_variant	Intron 1 of 11	1	NM_201253.3	ENSP00000356370.3

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53380 AN: 151902 Hom.: 11864 Cov.: 32

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.478

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.381

GnomAD3 exomes AF: 0.448 AC: 110331 AN: 246166 Hom.: 27368 AF XY: 0.444 AC XY: 59330 AN XY: 133750

Gnomad AFR exome AF: 0.0778

Gnomad AMR exome AF: 0.576

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.791

Gnomad SAS exome AF: 0.413

Gnomad FIN exome AF: 0.516

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.416

GnomAD4 exome AF: 0.420 AC: 604539 AN: 1438226 Hom.: 133316 Cov.: 29 AF XY: 0.420 AC XY: 301211 AN XY: 716906

Gnomad4 AFR exome AF: 0.0692

Gnomad4 AMR exome AF: 0.574

Gnomad4 ASJ exome AF: 0.366

Gnomad4 EAS exome AF: 0.774

Gnomad4 SAS exome AF: 0.414

Gnomad4 FIN exome AF: 0.506

Gnomad4 NFE exome AF: 0.411

Gnomad4 OTH exome AF: 0.409

GnomAD4 genome AF: 0.351 AC: 53385 AN: 152020 Hom.: 11869 Cov.: 32 AF XY: 0.362 AC XY: 26902 AN XY: 74302

Gnomad4 AFR AF: 0.0879

Gnomad4 AMR AF: 0.479

Gnomad4 ASJ AF: 0.369

Gnomad4 EAS AF: 0.781

Gnomad4 SAS AF: 0.431

Gnomad4 FIN AF: 0.518

Gnomad4 NFE AF: 0.420

Gnomad4 OTH AF: 0.379

Alfa AF: 0.282 Hom.: 1220

Bravo AF: 0.340

Asia WGS AF: 0.542 AC: 1887 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 13, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 25, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis 8 Benign:2

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Pigmented paravenous retinochoroidal atrophy Benign:2

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.70
CADD	Benign	7.7
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000061
dbscSNV1_RF	Benign	0.0020
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: rs12042179; hg19: chr1-197297540;