22-42127526-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -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).

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

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: 7.72

Publications

50 publications found

Variant links:

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]

CYP2D6 links:

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

NDUFA6-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, 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 rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.1094G>A	p.Arg365His	missense_variant	Exon 7 of 9	ENST00000645361.2	NP_000097.3	P10635-1C1ID52Q5Y7H2
CYP2D6	NM_001025161.3 link	c.941G>A	p.Arg314His	missense_variant	Exon 6 of 8		NP_001020332.2	P10635-2Q5Y7H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2 link	c.1094G>A	p.Arg365His	missense_variant	Exon 7 of 9		NM_000106.6	ENSP00000496150.1		P10635-1

Frequencies

GnomAD3 genomes

AF:

0.0535

AC:

7199

AN:

134436

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0917

AC:

21064

AN:

229594

AF XY:

0.0934

show subpopulations

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 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.:

Cov.:

AF XY:

0.0509

AC XY:

30816

AN XY:

605814

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00602

AC:

194

AN:

32222

American (AMR)

AF:

0.0125

AC:

516

AN:

41256

Ashkenazi Jewish (ASJ)

AF:

0.0362

AC:

766

AN:

21182

East Asian (EAS)

AF:

0.000278

AC:

AN:

39596

South Asian (SAS)

AF:

0.0180

AC:

1407

AN:

78310

European-Finnish (FIN)

AF:

0.0307

AC:

1462

AN:

47570

Middle Eastern (MID)

AF:

0.0328

AC:

170

AN:

5178

European-Non Finnish (NFE)

AF:

0.0619

AC:

55580

AN:

897914

Other (OTH)

AF:

0.0391

AC:

1994

AN:

51036

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.273

Heterozygous variant carriers

6513

13027

19540

26054

32567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0535

AC:

7198

AN:

134560

Hom.:

Cov.:

AF XY:

0.0497

AC XY:

3285

AN XY:

66160

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0136

AC:

540

AN:

39686

American (AMR)

AF:

0.0419

AC:

577

AN:

13782

Ashkenazi Jewish (ASJ)

AF:

0.0642

AC:

177

AN:

2756

East Asian (EAS)

AF:

0.000389

AC:

AN:

5138

South Asian (SAS)

AF:

0.0333

AC:

146

AN:

4382

European-Finnish (FIN)

AF:

0.0395

AC:

379

AN:

9586

Middle Eastern (MID)

AF:

0.0310

AC:

AN:

258

European-Non Finnish (NFE)

AF:

0.0916

AC:

5157

AN:

56324

Other (OTH)

AF:

0.0557

AC:

105

AN:

1886

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.288

Heterozygous variant carriers

605

1210

1814

2419

3024

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.123

Hom.:

ExAC

AF:

0.120

AC:

14572

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Tramadol response

Other:1

Apr 28, 2018

Bruce Budowle Laboratory, University of North Texas Health Science Center

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:research

- 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

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

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

LIST_S2

Uncertain

0.87

.;.;D;D;D

MetaRNN

Benign

0.019

T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Pathogenic

4.7

H;H;H;.;.

PhyloP100

7.7

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-4.5

.;.;D;.;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

.;.;D;.;D

Sift4G

Pathogenic

0.0010

.;.;D;D;D

Vest4

0.34, 0.49, 0.53

MPC

0.61

ClinPred

0.11

GERP RS

4.9

Varity_R

0.69

gMVP

0.85

Mutation Taster

=91/9

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

22-42127526-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over