1-197427552-G-C

Position:

• chr1-197427552-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BP4

The NM_201253.3(CRB1):​c.2227G>C​(p.Val743Leu) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRB1 NM_201253.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.60

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_201253.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-197427552-G-C is Pathogenic according to our data. Variant chr1-197427552-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27109838). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRB1	NM_201253.3	c.2227G>C	p.Val743Leu	missense_variant	7/12	ENST00000367400.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRB1	ENST00000367400.8	c.2227G>C	p.Val743Leu	missense_variant	7/12	1	NM_201253.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 12 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Mar 12, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Leber congenital amaurosis 8 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.019	T;.;T;.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	D;.;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.8	.;L;L;.;.
MutationTaster	Benign	0.86	D;D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.76	N;.;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.51	T;.;T;T;T
Sift4G	Benign	0.55	T;.;T;T;D
Polyphen		0.90	P;.;P;P;.
Vest4		0.26
MutPred		0.58		.;Gain of catalytic residue at S738 (P = 0.3167);Gain of catalytic residue at S738 (P = 0.3167);.;.;
MVP		0.68
MPC		0.18
ClinPred		0.56	D
GERP RS		3.9
Varity_R		0.070
gMVP		0.75

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: rs863224862; hg19: chr1-197396682;