rs62645749

chr1-197328965-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_201253.3(CRB1):c.614T>C(p.Ile205Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000494 in 1,613,878 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (1 hom.)
• Consequence: CRB1 NM_201253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:7 O:1
• Conservation: PhyloP100: 5.68

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a disulfide_bond (size 15) in uniprot entity CRUM1_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_201253.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.09901568).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRB1	NM_201253.3	c.614T>C	p.Ile205Thr	missense_variant	2/12	ENST00000367400.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRB1	ENST00000367400.8	c.614T>C	p.Ile205Thr	missense_variant	2/12	1	NM_201253.3	P1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000599 AC: 150 AN: 250566 Hom.: 1 AF XY: 0.000531 AC XY: 72 AN XY: 135596

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000557

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000494 AC: 722 AN: 1461536 Hom.: 1 Cov.: 33 AF XY: 0.000470 AC XY: 342 AN XY: 727072

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000471

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74506

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000532 Hom.: 1

Bravo AF: 0.000646

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.00120

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Retinitis pigmentosa Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely pathogenic, flagged submission	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Leber congenital amaurosis 8 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Leber congenital amaurosis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Leber congenital amaurosis Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 24, 2020

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Pigmented paravenous retinochoroidal atrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	24
Dann	Benign	0.25
Eigen	Benign	0.032
Eigen_PC	Benign	-0.0084
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;.;D;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.099	T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.64	N;.;N;N;N
MutationTaster	Benign	0.64	D;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.0	D;D;.;D;N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.027	D;T;.;T;T
Sift4G	Uncertain	0.0040	D;T;.;D;T
Polyphen		0.99, 0.98, 0.16	.;D;.;D;B
Vest4		0.58
MVP		0.93
MPC		0.25
ClinPred		0.054	T
GERP RS		4.4
Varity_R		0.17
gMVP		0.55

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: rs62645749; hg19: chr1-197298095;