chr10-84194761-A-G
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PS1_ModeratePM2PP5
The NM_033100.4(CDHR1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 1,519,498 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
CDHR1
NM_033100.4 start_lost
NM_033100.4 start_lost
Scores
3
1
9
Clinical Significance
Conservation
PhyloP100: 2.51
Genes affected
CDHR1 (HGNC:14550): (cadherin related family member 1) This gene belongs to the cadherin superfamily of calcium-dependent cell adhesion molecules. The encoded protein is a photoreceptor-specific cadherin that plays a role in outer segment disc morphogenesis. Mutations in this gene are associated with inherited retinal dystrophies. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_033100.4 (CDHR1) was described as [Pathogenic] in ClinVar as 812258
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 10-84194761-A-G is Pathogenic according to our data. Variant chr10-84194761-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193474.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=2, Uncertain_significance=1}. Variant chr10-84194761-A-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDHR1 | NM_033100.4 | c.1A>G | p.Met1? | start_lost | 1/17 | ENST00000623527.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDHR1 | ENST00000623527.4 | c.1A>G | p.Met1? | start_lost | 1/17 | 1 | NM_033100.4 | P2 | |
CDHR1 | ENST00000332904.7 | c.1A>G | p.Met1? | start_lost | 1/17 | 1 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152120Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000171 AC: 2AN: 116880Hom.: 0 AF XY: 0.0000155 AC XY: 1AN XY: 64500
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GnomAD4 exome AF: 0.0000271 AC: 37AN: 1367378Hom.: 0 Cov.: 31 AF XY: 0.0000282 AC XY: 19AN XY: 674492
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 05, 2023 | Disruption of the initiator codon has been observed in individuals with retinal dystrophy (PMID: 26306921, 32037395, 32681094; Invitae). This sequence change affects the initiator methionine of the CDHR1 mRNA. The next in-frame methionine is located at codon 39. This variant is present in population databases (rs794726954, gnomAD 0.005%). ClinVar contains an entry for this variant (Variation ID: 193474). For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 28, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 19, 2021 | Described in an individual with adult-onset macular dystrophy and reduced visual acuity who also harbored a synonymous variant in CDHR1 in published literature (Ba-Abbad et al., 2020); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32681094) - |
Cone-rod dystrophy 15 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | DBGen Ocular Genomics | Jun 01, 2021 | - - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Apr 01, 2021 | The p.Met1? variant in CDHR1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
Sift4G
Pathogenic
D;D
Polyphen
B;B
Vest4
MutPred
Loss of catalytic residue at M1 (P = 0.0029);Loss of catalytic residue at M1 (P = 0.0029);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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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