1-197427631-G-C

Position:

• chr1-197427631-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_201253.3(CRB1):​c.2306G>C​(p.Arg769Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. R769H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRB1 NM_201253.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.247

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr1-197427630-CGC-CAG is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.35268608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRB1	NM_201253.3	c.2306G>C	p.Arg769Pro	missense_variant	7/12	ENST00000367400.8	NP_957705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRB1	ENST00000367400.8	c.2306G>C	p.Arg769Pro	missense_variant	7/12	1	NM_201253.3	ENSP00000356370.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

ClinVar contains an entry for this variant (Variation ID: 849050). This variant has not been reported in the literature in individuals affected with CRB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 769 of the CRB1 protein (p.Arg769Pro). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CRB1 protein function. 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	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.38
DANN	Benign	0.94
DEOGEN2	Benign	0.26	T;.;T;.;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.54	T;.;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.34	.;N;N;.;.
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.9	N;.;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.24	T;.;T;T;T
Sift4G	Benign	0.34	T;.;T;T;T
Polyphen		0.24	B;.;P;P;.
Vest4		0.29
MutPred		0.63		.;Loss of MoRF binding (P = 0.0166);Loss of MoRF binding (P = 0.0166);.;.;
MVP		0.75
MPC		0.091
ClinPred		0.13	T
GERP RS		0.56
Varity_R		0.22
gMVP		0.78

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: rs62636287; hg19: chr1-197396761;