chr1-197427705-C-A

Position:

• chr1-197427705-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_201253.3(CRB1):​c.2380C>A​(p.His794Asn) 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 pathogenic 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. H794Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRB1 NM_201253.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69

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 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 1 benign, 4 uncertain in NM_201253.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRB1	NM_201253.3	c.2380C>A	p.His794Asn	missense_variant	7/12	ENST00000367400.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRB1	ENST00000367400.8	c.2380C>A	p.His794Asn	missense_variant	7/12	1	NM_201253.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Invitae

Jun 12, 2017

In summary, this variant has uncertain impact on CRB1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant has not been reported in the literature in individuals with a CRB1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with asparagine at codon 794 of the CRB1 protein (p.His794Asn). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D;.;D;.;T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.71	T;.;T;T;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.9	.;L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.3	D;.;D;D;D
REVEL	Uncertain	0.63
Sift	Benign	0.079	T;.;T;D;D
Sift4G	Benign	0.14	T;.;T;D;D
Polyphen		0.80	P;.;B;D;.
Vest4		0.35
MutPred		0.69		.;Loss of ubiquitination at K799 (P = 0.1216);Loss of ubiquitination at K799 (P = 0.1216);.;.;
MVP		0.94
MPC		0.036
ClinPred		0.70	D
GERP RS		5.5
Varity_R		0.23
gMVP		0.92

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: rs1294237377; hg19: chr1-197396835;