22-42127526-C-T

Position:

• chr22-42127526-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BP4_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
• Clinical Significance: drug response no assertion criteria provided O:1
• 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]

NDUFA6-DT (HGNC:45273): (NDUFA6 divergent transcript)

ACMG classification

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: 7199 AN: 134436 Hom.: 5 Cov.: 34 FAILED QC

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.0419

Gnomad ASJ AF: 0.0642

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.0338

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.0324

Gnomad NFE AF: 0.0915

Gnomad OTH AF: 0.0564

GnomAD3 exomes AF: 0.0917 AC: 21064 AN: 229594 Hom.: 25 AF XY: 0.0934 AC XY: 11620 AN XY: 124470

Gnomad AFR exome AF: 0.0244

Gnomad AMR exome AF: 0.0548

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.000819

Gnomad SAS exome AF: 0.0567

Gnomad FIN exome AF: 0.0808

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.0931

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0511 AC: 62100 AN: 1214264 Hom.: 58 Cov.: 64 AF XY: 0.0509 AC XY: 30816 AN XY: 605814

Gnomad4 AFR exome AF: 0.00602

Gnomad4 AMR exome AF: 0.0125

Gnomad4 ASJ exome AF: 0.0362

Gnomad4 EAS exome AF: 0.000278

Gnomad4 SAS exome AF: 0.0180

Gnomad4 FIN exome AF: 0.0307

Gnomad4 NFE exome AF: 0.0619

Gnomad4 OTH exome AF: 0.0391

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0535 AC: 7198 AN: 134560 Hom.: 5 Cov.: 34 AF XY: 0.0497 AC XY: 3285 AN XY: 66160

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.0419

Gnomad4 ASJ AF: 0.0642

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.0333

Gnomad4 FIN AF: 0.0395

Gnomad4 NFE AF: 0.0916

Gnomad4 OTH AF: 0.0557

Alfa AF: 0.0984 Hom.: 91

ExAC AF: 0.120 AC: 14572

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T;T;T;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.019	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Pathogenic	4.7	H;H;H;.;.
MutationTaster	Benign	3.8e-9	P;P;P
PrimateAI	Benign	0.47	T
Vest4		0.34, 0.49, 0.53
MPC		0.61
ClinPred		0.11	T
GERP RS		4.9
Varity_R		0.69
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1058172; hg19: chr22-42523528; COSMIC: COSV62242932; COSMIC: COSV62242932;