22-42130761-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000106.6(CYP2D6):c.31G>A(p.Val11Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0476 in 1,585,140 control chromosomes in the GnomAD database, including 4,366 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 311 hom., cov: 31)

Exomes 𝑓: 0.049 ( 4055 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: -4.72

Publications

86 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001912564).

BP6

Variant 22-42130761-C-T is Benign according to our data. Variant chr22-42130761-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 676320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.31G>A	p.Val11Met	missense_variant	Exon 1 of 9	ENST00000645361.2	NP_000097.3	P10635-1C1ID52Q5Y7H2
CYP2D6	NM_001025161.3 link	c.31G>A	p.Val11Met	missense_variant	Exon 1 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.31G>A	p.Val11Met	missense_variant	Exon 1 of 9		NM_000106.6	ENSP00000496150.1		P10635-1

Frequencies

GnomAD3 genomes

AF:

0.0388

AC:

5857

AN:

151124

Hom.:

312

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00927

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.0223

Gnomad ASJ

AF:

0.0337

Gnomad EAS

AF:

0.00271

Gnomad SAS

AF:

0.00751

Gnomad FIN

AF:

0.0693

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0611

Gnomad OTH

AF:

0.0366

GnomAD2 exomes

AF:

0.0380

AC:

7999

AN:

210718

AF XY:

0.0381

show subpopulations

Gnomad AFR exome

AF:

0.00856

Gnomad AMR exome

AF:

0.0226

Gnomad ASJ exome

AF:

0.0359

Gnomad EAS exome

AF:

0.00220

Gnomad FIN exome

AF:

0.0666

Gnomad NFE exome

AF:

0.0563

Gnomad OTH exome

AF:

0.0446

GnomAD4 exome

AF:

0.0485

AC:

69567

AN:

1433902

Hom.:

4055

Cov.:

AF XY:

0.0481

AC XY:

34204

AN XY:

710904

show subpopulations

African (AFR)

AF:

0.00810

AC:

265

AN:

32734

American (AMR)

AF:

0.0237

AC:

982

AN:

41356

Ashkenazi Jewish (ASJ)

AF:

0.0360

AC:

925

AN:

25670

East Asian (EAS)

AF:

0.00131

AC:

AN:

38816

South Asian (SAS)

AF:

0.00802

AC:

662

AN:

82570

European-Finnish (FIN)

AF:

0.0654

AC:

3363

AN:

51452

Middle Eastern (MID)

AF:

0.0317

AC:

175

AN:

5516

European-Non Finnish (NFE)

AF:

0.0553

AC:

60604

AN:

1096580

Other (OTH)

AF:

0.0429

AC:

2540

AN:

59208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

3168

6336

9505

12673

15841

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2044

4088

6132

8176

10220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0387

AC:

5857

AN:

151238

Hom.:

311

Cov.:

AF XY:

0.0380

AC XY:

2812

AN XY:

73922

show subpopulations

African (AFR)

AF:

0.00924

AC:

379

AN:

41012

American (AMR)

AF:

0.0222

AC:

338

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.0337

AC:

117

AN:

3470

East Asian (EAS)

AF:

0.00271

AC:

AN:

5160

South Asian (SAS)

AF:

0.00773

AC:

AN:

4788

European-Finnish (FIN)

AF:

0.0693

AC:

733

AN:

10582

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0612

AC:

4141

AN:

67716

Other (OTH)

AF:

0.0363

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

215

430

645

860

1075

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0532

Hom.:

204

Bravo

AF:

0.0343

TwinsUK

AF:

0.0523

AC:

194

ALSPAC

AF:

0.0480

AC:

185

ESP6500AA

AF:

0.00820

AC:

ESP6500EA

AF:

0.0581

AC:

499

ExAC

AF:

0.0345

AC:

4138

Asia WGS

AF:

0.00783

AC:

AN:

3464

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 12, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Benign

0.16

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.30

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.016

T;T;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.73

.;.;T;T

MetaRNN

Benign

0.0019

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N;N;N

PhyloP100

-4.7

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.4

.;.;N;N

REVEL

Benign

0.036

Sift

Benign

0.11

.;.;T;T

Sift4G

Benign

0.14

.;.;T;T

Vest4

0.015, 0.052

MPC

0.11

ClinPred

0.0050

GERP RS

-3.0

PromoterAI

0.051

Neutral

(source)

Varity_R

0.012

gMVP

0.35

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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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