Genetic Variant CYP2D6:p.Val136Met (chr22-42129132-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000106.6(CYP2D6):c.406G>A(p.Val136Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,609,922 control chromosomes in the GnomAD database, including 523 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.026 ( 357 hom., cov: 33)

Exomes 𝑓: 0.0027 ( 166 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.89

Publications

60 publications found

Variant links:

COSMIC-nc: COSV62243446

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002351731).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.406G>A	p.Val136Met	missense_variant	Exon 3 of 9	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3 link	c.353-188G>A		intron_variant	Intron 2 of 7		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2 link	c.406G>A	p.Val136Met	missense_variant	Exon 3 of 9		NM_000106.6	ENSP00000496150.1

Frequencies

GnomAD3 genomes

AF:

0.0261

AC:

3959

AN:

151462

Hom.:

357

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0909

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00951

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000581

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000575

Gnomad OTH

AF:

0.0179

GnomAD2 exomes

AF:

0.00668

AC:

1640

AN:

245456

AF XY:

0.00502

show subpopulations

Gnomad AFR exome

AF:

0.0951

Gnomad AMR exome

AF:

0.00390

Gnomad ASJ exome

AF:

0.00210

Gnomad EAS exome

AF:

0.000504

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000233

Gnomad OTH exome

AF:

0.00284

GnomAD4 exome

AF:

0.00265

AC:

3868

AN:

1458348

Hom.:

166

Cov.:

AF XY:

0.00227

AC XY:

1646

AN XY:

725544

show subpopulations

African (AFR)

AF:

0.0916

AC:

3051

AN:

33314

American (AMR)

AF:

0.00464

AC:

207

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

26102

East Asian (EAS)

AF:

0.000152

AC:

AN:

39592

South Asian (SAS)

AF:

0.000314

AC:

AN:

86102

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52430

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000154

AC:

171

AN:

1110186

Other (OTH)

AF:

0.00560

AC:

337

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

216

432

648

864

1080

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<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:

0.0262

AC:

3967

AN:

151574

Hom.:

357

Cov.:

AF XY:

0.0244

AC XY:

1808

AN XY:

74090

show subpopulations

African (AFR)

AF:

0.0908

AC:

3736

AN:

41138

American (AMR)

AF:

0.00950

AC:

145

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.000582

AC:

AN:

5154

South Asian (SAS)

AF:

0.000208

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000575

AC:

AN:

67846

Other (OTH)

AF:

0.0177

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

149

298

448

597

746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.00490

Hom.:

Bravo

AF:

0.0307

ESP6500AA

AF:

0.0877

AC:

356

ESP6500EA

AF:

0.000240

AC:

ExAC

AF:

0.00830

AC:

1003

Asia WGS

AF:

0.00579

AC:

AN:

3468

EpiCase

AF:

0.000273

EpiControl

AF:

0.000238

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

0.35

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0053

T;T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.85

.;.;D;D

MetaRNN

Benign

0.0024

T;T;T;T

PhyloP100

-1.9

PROVEAN

Benign

-1.4

.;.;N;.

Sift

Benign

0.042

.;.;D;.

Sift4G

Uncertain

0.022

.;.;D;D

Vest4

0.16, 0.16

MVP

0.26

ClinPred

0.0070

GERP RS

-8.2

Varity_R

0.11

gMVP

0.44

Mutation Taster

=97/3

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

Computational scores

Splicing

Publications

Other links and lift over