chr1-197427787-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_201253.3(CRB1):​c.2462C>G​(p.Thr821Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. T821M) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CRB1
NM_201253.3 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.337
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a domain Laminin G-like 2 (size 171) in uniprot entity CRUM1_HUMAN there are 53 pathogenic changes around while only 2 benign (96%) 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 chr1-197427787-C-T is described in Lovd as [Pathogenic].
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CRB1NM_201253.3 linkuse as main transcriptc.2462C>G p.Thr821Arg missense_variant 7/12 ENST00000367400.8 NP_957705.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CRB1ENST00000367400.8 linkuse as main transcriptc.2462C>G p.Thr821Arg missense_variant 7/121 NM_201253.3 ENSP00000356370 P1P82279-1

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
LINK: link

Submissions by phenotype

Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 24, 2022In 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 26047050). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 821 of the CRB1 protein (p.Thr821Arg). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.42
CADD
Uncertain
24
DANN
Benign
0.93
DEOGEN2
Uncertain
0.43
T;.;D;.;T
Eigen
Benign
-0.46
Eigen_PC
Benign
-0.59
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.66
T;.;T;T;T
M_CAP
Pathogenic
0.56
D
MetaRNN
Uncertain
0.53
D;D;D;D;D
MetaSVM
Benign
-0.52
T
MutationAssessor
Uncertain
2.5
.;M;M;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N
PrimateAI
Benign
0.28
T
PROVEAN
Uncertain
-2.4
N;.;N;N;N
REVEL
Uncertain
0.36
Sift
Benign
0.54
T;.;T;T;T
Sift4G
Benign
0.42
T;.;T;T;D
Polyphen
0.99
D;.;D;D;.
Vest4
0.71
MutPred
0.79
.;Loss of methylation at K826 (P = 0.0707);Loss of methylation at K826 (P = 0.0707);.;.;
MVP
0.81
MPC
0.19
ClinPred
0.40
T
GERP RS
4.0
Varity_R
0.096
gMVP
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.95
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.95
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-197396917; API