rs61748441
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Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1
The NM_000554.6(CRX):c.365G>A(p.Gly122Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,613,832 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0061 ( 25 hom., cov: 31)
Exomes 𝑓: 0.0028 ( 208 hom. )
Consequence
CRX
NM_000554.6 missense
NM_000554.6 missense
Scores
5
12
Clinical Significance
Conservation
PhyloP100: 2.29
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 Benign. Variant got -18 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
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0019873083).
BP6
?
Variant 19-47839432-G-A is Benign according to our data. Variant chr19-47839432-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 99604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-47839432-G-A is described in Lovd as [Likely_pathogenic].
BA1
?
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRX | NM_000554.6 | c.365G>A | p.Gly122Asp | missense_variant | 4/4 | ENST00000221996.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRX | ENST00000221996.12 | c.365G>A | p.Gly122Asp | missense_variant | 4/4 | 2 | NM_000554.6 | P1 | |
CRX | ENST00000613299.1 | c.*87G>A | 3_prime_UTR_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00610 AC: 927AN: 152090Hom.: 25 Cov.: 31
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GnomAD3 exomes AF: 0.0126 AC: 3155AN: 250400Hom.: 177 AF XY: 0.00949 AC XY: 1287AN XY: 135554
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GnomAD4 exome AF: 0.00282 AC: 4115AN: 1461624Hom.: 208 Cov.: 31 AF XY: 0.00241 AC XY: 1751AN XY: 727128
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GnomAD4 genome ? AF: 0.00612 AC: 932AN: 152208Hom.: 25 Cov.: 31 AF XY: 0.00679 AC XY: 505AN XY: 74406
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4Other:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 11, 2023 | - - |
not provided, no classification provided | literature only | Retina International | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 15, 2019 | This variant is associated with the following publications: (PMID: 31626798, 28512305, 27535533, 16123401) - |
Likely benign, no assertion criteria provided | literature only | Department of Ophthalmology and Visual Sciences Kyoto University | - | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 13, 2016 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 27, 2013 | - - |
Central core myopathy Benign:1
Benign, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | - | The p.Gly122Asp variant in CRX has not been previously reported in individuals with Leber congenital amaurosis but was included on an array of >300 variants for this disease (PMID: 16123401), and has also been identified in >9% of Latino chromosomes and 60 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for Leber congenital amaurosis. - |
Cone-rod dystrophy 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Leber congenital amaurosis 7 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Retinal dystrophy Benign:1
Benign, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Retinitis pigmentosa Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MPC
ClinPred
T
GERP RS
Varity_R
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