rs1553260517

Positions:

• chr1-197421845-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_201253.3(CRB1):​c.2017A>G​(p.Lys673Glu) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRB1 NM_201253.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.56

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 4 ACMG points.

• PM1: In a domain EGF-like 12 (size 36) in uniprot entity CRUM1_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_201253.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-197421845-A-G is Pathogenic according to our data. Variant chr1-197421845-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438072.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-197421845-A-G is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.21741042). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRB1	NM_201253.3	c.2017A>G	p.Lys673Glu	missense_variant	6/12	ENST00000367400.8	NP_957705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRB1	ENST00000367400.8	c.2017A>G	p.Lys673Glu	missense_variant	6/12	1	NM_201253.3	ENSP00000356370	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	.;T;.;T;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.69	T;T;.;T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.77	N;.;N;N;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N;N;.;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.071	T;D;.;D;D;D
Sift4G	Benign	0.15	T;T;.;T;T;D
Polyphen		0.99, 1.0, 1.0	.;D;.;D;D;.
Vest4		0.16
MutPred		0.45		Loss of ubiquitination at K673 (P = 0.011);.;Loss of ubiquitination at K673 (P = 0.011);Loss of ubiquitination at K673 (P = 0.011);.;.;
MVP		0.84
MPC		0.041
ClinPred		0.50	T
GERP RS		4.7
Varity_R		0.33
gMVP		0.64

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: rs1553260517; hg19: chr1-197390975;