1-197429611-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_201253.3(CRB1):​c.2839G>C​(p.Glu947Gln) variant causes a missense change involving the alteration of a 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. E947K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CRB1
NM_201253.3 missense

Scores

3
10
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.41
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 6 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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 chr1-197429611-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CRB1NM_201253.3 linkc.2839G>C p.Glu947Gln missense_variant Exon 8 of 12 ENST00000367400.8 NP_957705.1 P82279-1A0A7D6VM04

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CRB1ENST00000367400.8 linkc.2839G>C p.Glu947Gln missense_variant Exon 8 of 12 1 NM_201253.3 ENSP00000356370.3 P82279-1

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
Jun 18, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 947 of the CRB1 protein (p.Glu947Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CRB1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.060
T;.;D;.;T
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.86
D;.;D;D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Uncertain
0.62
D;D;D;D;D
MetaSVM
Uncertain
0.41
D
MutationAssessor
Pathogenic
3.0
.;M;M;.;.
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-2.2
N;.;N;N;N
REVEL
Uncertain
0.52
Sift
Uncertain
0.0080
D;.;D;D;D
Sift4G
Benign
0.15
T;.;T;T;T
Polyphen
1.0
D;.;D;D;.
Vest4
0.49
MutPred
0.45
.;Gain of catalytic residue at C948 (P = 0.2068);Gain of catalytic residue at C948 (P = 0.2068);.;.;
MVP
0.95
MPC
0.17
ClinPred
0.94
D
GERP RS
5.5
Varity_R
0.24
gMVP
0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-197398741; API