chr19-47834454-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_000554.6(CRX):c.11A>G(p.Tyr4Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
CRX
NM_000554.6 missense
NM_000554.6 missense
Scores
9
4
3
Clinical Significance
Conservation
PhyloP100: 6.86
Genes affected
CRX (HGNC:2383): (cone-rod homeobox) The protein encoded by this gene is a photoreceptor-specific transcription factor which plays a role in the differentiation of photoreceptor cells. This homeodomain protein is necessary for the maintenance of normal cone and rod function. Mutations in this gene are associated with photoreceptor degeneration, Leber congenital amaurosis type III and the autosomal dominant cone-rod dystrophy 2. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM1
?
In a chain Cone-rod homeobox protein (size 298) in uniprot entity CRX_HUMAN there are 56 pathogenic changes around while only 17 benign (77%) in NM_000554.6
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.837
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRX | NM_000554.6 | c.11A>G | p.Tyr4Cys | missense_variant | 2/4 | ENST00000221996.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRX | ENST00000221996.12 | c.11A>G | p.Tyr4Cys | missense_variant | 2/4 | 2 | NM_000554.6 | P1 | |
CRX | ENST00000556527.1 | n.78-1789A>G | intron_variant, non_coding_transcript_variant | 1 | |||||
CRX | ENST00000566686.5 | c.11A>G | p.Tyr4Cys | missense_variant | 2/3 | 5 | |||
CRX | ENST00000613299.1 | c.11A>G | p.Tyr4Cys | missense_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251482Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135914
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461768Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727196
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CRX protein function. ClinVar contains an entry for this variant (Variation ID: 1023327). This missense change has been observed in individual(s) with clinical features of CRX-related conditions (Invitae). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 4 of the CRX protein (p.Tyr4Cys). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;.
Sift
Pathogenic
D;D;D;.
Sift4G
Pathogenic
D;D;D;D
Polyphen
1.0
.;D;D;.
Vest4
0.62, 0.79, 0.86
MutPred
Gain of catalytic residue at M2 (P = 0.0015);Gain of catalytic residue at M2 (P = 0.0015);Gain of catalytic residue at M2 (P = 0.0015);Gain of catalytic residue at M2 (P = 0.0015);
MVP
MPC
0.81
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at