chr22-42127526-C-T
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BP4_Strong
The NM_000106.6(CYP2D6):c.1094G>A(p.Arg365His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.
Frequency
Genomes: 𝑓 0.053 ( 5 hom., cov: 34)
Exomes 𝑓: 0.051 ( 58 hom. )
Failed GnomAD Quality Control
Consequence
CYP2D6
NM_000106.6 missense
NM_000106.6 missense
Scores
6
2
5
Clinical Significance
Conservation
PhyloP100: 7.72
Genes affected
CYP2D6 (HGNC:2625): (cytochrome P450 family 2 subfamily D member 6) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and is known to metabolize as many as 25% of commonly prescribed drugs. Its substrates include antidepressants, antipsychotics, analgesics and antitussives, beta adrenergic blocking agents, antiarrythmics and antiemetics. The gene is highly polymorphic in the human population; certain alleles result in the poor metabolizer phenotype, characterized by a decreased ability to metabolize the enzyme's substrates. Some individuals with the poor metabolizer phenotype have no functional protein since they carry 2 null alleles whereas in other individuals the gene is absent. This gene can vary in copy number and individuals with the ultrarapid metabolizer phenotype can have 3 or more active copies of the gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP3
Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.018501878).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP2D6 | NM_000106.6 | c.1094G>A | p.Arg365His | missense_variant | 7/9 | ENST00000645361.2 | |
CYP2D6 | NM_001025161.3 | c.941G>A | p.Arg314His | missense_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP2D6 | ENST00000645361.2 | c.1094G>A | p.Arg365His | missense_variant | 7/9 | NM_000106.6 | P1 | ||
NDUFA6-DT | ENST00000439129.5 | n.1718+2119C>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 7199AN: 134436Hom.: 5 Cov.: 34 FAILED QC
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GnomAD3 exomes AF: 0.0917 AC: 21064AN: 229594Hom.: 25 AF XY: 0.0934 AC XY: 11620AN XY: 124470
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0511 AC: 62100AN: 1214264Hom.: 58 Cov.: 64 AF XY: 0.0509 AC XY: 30816AN XY: 605814
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GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0535 AC: 7198AN: 134560Hom.: 5 Cov.: 34 AF XY: 0.0497 AC XY: 3285AN XY: 66160
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ClinVar
Significance: drug response
Submissions summary: Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Tramadol response Other:1
drug response, no assertion criteria provided | research | Bruce Budowle Laboratory, University of North Texas Health Science Center | Apr 28, 2018 | - T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1 |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;T;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H;H;H;.;.
MutationTaster
Benign
P;P;P
PrimateAI
Benign
T
Vest4
0.34, 0.49, 0.53
MPC
0.61
ClinPred
T
GERP RS
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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