NM_000106.6:c.1012G>A

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.1012G>A(p.Val338Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00469 in 1,611,318 control chromosomes in the GnomAD database, including 366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★).

Frequency

Genomes: 𝑓 0.025 ( 230 hom., cov: 34)

Exomes 𝑓: 0.0026 ( 136 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.02

Publications

112 publications found

Variant links:

COSMIC-nc: COSV62243426

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=0.019043714).

BP6

Variant 22-42127608-C-T is Benign according to our data. Variant chr22-42127608-C-T is described in ClinVar as Likely_benign|other. ClinVar VariationId is 598263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0836 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000106.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	NM_000106.6	MANE Select	c.1012G>A	p.Val338Met	missense	Exon 7 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.859G>A	p.Val287Met	missense	Exon 6 of 8	NP_001020332.2	P10635-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP2D6	ENST00000645361.2	MANE Select	c.1012G>A	p.Val338Met	missense	Exon 7 of 9	ENSP00000496150.1	P10635-1
CYP2D6	ENST00000359033.4	TSL:1	c.859G>A	p.Val287Met	missense	Exon 6 of 8	ENSP00000351927.4	P10635-2
CYP2D6	ENST00000360124.10	TSL:1	n.*87G>A		non_coding_transcript_exon	Exon 6 of 8	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes

AF:

0.0248

AC:

3747

AN:

151366

Hom.:

231

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0860

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00919

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000604

Gnomad OTH

AF:

0.0188

GnomAD2 exomes

AF:

0.00673

AC:

1688

AN:

250912

AF XY:

0.00482

show subpopulations

Gnomad AFR exome

AF:

0.0918

Gnomad AMR exome

AF:

0.00382

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000256

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00261

AC:

3807

AN:

1459840

Hom.:

136

Cov.:

AF XY:

0.00223

AC XY:

1620

AN XY:

726248

show subpopulations

African (AFR)

AF:

0.0898

AC:

2991

AN:

33300

American (AMR)

AF:

0.00465

AC:

208

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.000267

AC:

AN:

86130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000163

AC:

181

AN:

1110540

Other (OTH)

AF:

0.00556

AC:

335

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

211

421

632

842

1053

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:

0.0248

AC:

3753

AN:

151478

Hom.:

230

Cov.:

AF XY:

0.0231

AC XY:

1708

AN XY:

74046

show subpopulations

African (AFR)

AF:

0.0859

AC:

3526

AN:

41026

American (AMR)

AF:

0.00918

AC:

140

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000208

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000604

AC:

AN:

67842

Other (OTH)

AF:

0.0186

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

144

288

431

575

719

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:

0.00570

Hom.:

Bravo

AF:

0.0300

ESP6500AA

AF:

0.0956

AC:

421

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00848

AC:

1029

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Likely benign; other

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.051

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.55

MutationAssessor

Pathogenic

3.5

PhyloP100

2.0

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.60

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0010

Vest4

0.59

MVP

0.72

MPC

0.54

ClinPred

0.076

GERP RS

3.9

Varity_R

0.15

gMVP

0.61

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over