1-197434706-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_201253.3(CRB1):​c.2843G>C​(p.Cys948Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C948R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CRB1
NM_201253.3 missense, splice_region

Scores

12
4
3
Splicing: ADA: 0.9985
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.00
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a disulfide_bond (size 15) in uniprot entity CRUM1_HUMAN there are 23 pathogenic changes around while only 1 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 chr1-197429614-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 427863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CRB1NM_201253.3 linkc.2843G>C p.Cys948Ser missense_variant, splice_region_variant Exon 9 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.2843G>C p.Cys948Ser missense_variant, splice_region_variant Exon 9 of 12 1 NM_201253.3 ENSP00000356370.3 P82279-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Retinal dystrophy Uncertain:1
Oct 01, 2023
Dept Of Ophthalmology, Nagoya University
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.53
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.31
T;.;D;.;T
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.84
T;.;D;D;D
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.2
.;M;M;.;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Pathogenic
-8.3
D;.;D;D;D
REVEL
Pathogenic
0.86
Sift
Pathogenic
0.0
D;.;D;D;D
Sift4G
Pathogenic
0.0
D;.;D;D;D
Polyphen
0.43
B;.;D;D;.
Vest4
0.94
MutPred
0.77
.;Gain of disorder (P = 0.2163);Gain of disorder (P = 0.2163);.;.;
MVP
0.98
MPC
0.25
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.91
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.96
SpliceAI score (max)
0.34
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.34
Position offset: 0

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: chr1-197403836; API