1-197421611-G-A

Position:

• chr1-197421611-G-A

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.1783G>A​(p.Ala595Thr) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRB1 NM_201253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 0.389

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 Laminin G-like 1 (size 185) in uniprot entity CRUM1_HUMAN there are 35 pathogenic changes around while only 0 benign (100%) in NM_201253.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-197421611-G-A is Pathogenic according to our data. Variant chr1-197421611-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190991.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12599233). . 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.1783G>A	p.Ala595Thr	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.1783G>A	p.Ala595Thr	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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

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Leber congenital amaurosis 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

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Retinitis pigmentosa 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.9
DANN	Benign	0.93
DEOGEN2	Benign	0.15	.;T;.;T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.73	T;T;.;T;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.16	N;.;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.76	N;N;.;N;N
REVEL	Benign	0.11
Sift	Benign	0.23	T;T;.;T;T
Sift4G	Benign	1.0	T;T;.;T;T
Polyphen		0.047, 0.058, 0.17	.;B;.;B;B
Vest4		0.026
MutPred		0.65		Gain of glycosylation at A595 (P = 0.0272);.;Gain of glycosylation at A595 (P = 0.0272);Gain of glycosylation at A595 (P = 0.0272);.;
MVP		0.76
MPC		0.034
ClinPred		0.46	T
GERP RS		1.6
Varity_R		0.031
gMVP		0.63

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: rs752212470; hg19: chr1-197390741; COSMIC: COSV66331230; COSMIC: COSV66331230;