rs201422368
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PVS1PM2PP5_Very_StrongBS1_Supporting
The NM_001349884.2(DRAM2):c.494G>A(p.Trp165Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000188 in 1,609,018 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00020 ( 0 hom. )
Consequence
DRAM2
NM_001349884.2 stop_gained
NM_001349884.2 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 5.75
Genes affected
DRAM2 (HGNC:28769): (DNA damage regulated autophagy modulator 2) The protein encoded by this gene binds microtubule-associated protein 1 light chain 3 and is required for autophagy. Defects in this gene are a cause of retinal dystrophy. In addition, two microRNAs (microRNA 125b-1 and microRNA 144) can bind to the mRNA of this gene and produce the disease state. [provided by RefSeq, Mar 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-111120539-C-T is Pathogenic according to our data. Variant chr1-111120539-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 192239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000204 (297/1457204) while in subpopulation NFE AF= 0.000261 (290/1109732). AF 95% confidence interval is 0.000236. There are 0 homozygotes in gnomad4_exome. There are 146 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DRAM2 | NM_001349884.2 | c.494G>A | p.Trp165Ter | stop_gained | 7/10 | ENST00000484310.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DRAM2 | ENST00000484310.6 | c.494G>A | p.Trp165Ter | stop_gained | 7/10 | 1 | NM_001349884.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 151814Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000364 AC: 9AN: 247452Hom.: 0 AF XY: 0.0000448 AC XY: 6AN XY: 133808
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GnomAD4 exome AF: 0.000204 AC: 297AN: 1457204Hom.: 0 Cov.: 31 AF XY: 0.000201 AC XY: 146AN XY: 724892
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cone-rod dystrophy 21 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 12, 2015 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 09, 2023 | This sequence change creates a premature translational stop signal (p.Trp165*) in the DRAM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DRAM2 are known to be pathogenic (PMID: 25983245). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 192239). This premature translational stop signal has been observed in individual(s) with retinal dystrophy (PMID: 25983245). This variant is present in population databases (rs201422368, gnomAD 0.007%). - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | reference population | Leeds Vision Research Group, University of Leeds | Nov 01, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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