rs145282040

chr1-197427454-A-Gchr1-197427454-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_201253.3(CRB1):c.2129A>G(p.Glu710Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000124 in 1,613,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E710V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CRB1 NM_201253.3 missense, splice_region
• Scores: Splicing: ADA: 0.0008250
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_201253.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-197427454-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRB1	NM_201253.3	c.2129A>G	p.Glu710Gly	missense_variant, splice_region_variant	7/12	ENST00000367400.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRB1	ENST00000367400.8	c.2129A>G	p.Glu710Gly	missense_variant, splice_region_variant	7/12	1	NM_201253.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151592 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461430 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151592 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73956

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 710 of the CRB1 protein (p.Glu710Gly). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CRB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1405755). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Glu710 amino acid residue in CRB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20591486, 20956273, 28041643, 28559085). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;D;.;T
Eigen	Benign	0.040
Eigen_PC	Benign	-0.032
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.73	T;.;T;T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.9	D;.;D;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D;.;D;D;D
Sift4G	Uncertain	0.0040	D;.;D;D;D
Polyphen		0.55	P;.;B;B;.
Vest4		0.52
MutPred		0.53		.;Loss of stability (P = 0.0246);Loss of stability (P = 0.0246);.;.;
MVP		0.86
MPC		0.046
ClinPred		0.97	D
GERP RS		3.4
Varity_R		0.27
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00083
dbscSNV1_RF	Benign	0.14
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: rs145282040; hg19: chr1-197396584; COSMIC: COSV66328456;