NM_000106.6:c.505G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 4P and 12B. PP3_StrongBP6_Very_StrongBS2

The NM_000106.6(CYP2D6):c.505G>A(p.Gly169Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,606,206 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign,other (★★).

Frequency

Genomes: 𝑓 0.00037 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 20 hom. )

Consequence

CYP2D6
NM_000106.6 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

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

Conservation

PhyloP100: -0.155

Publications

122 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 -8 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 22-42129033-C-T is Benign according to our data. Variant chr22-42129033-C-T is described in ClinVar as Likely_benign|other. ClinVar VariationId is 39399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 56 AD gene.

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.505G>A	p.Gly169Arg	missense splice_region	Exon 3 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.353-89G>A		intron	N/A	NP_001020332.2	P10635-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP2D6	ENST00000645361.2	MANE Select	c.505G>A	p.Gly169Arg	missense splice_region	Exon 3 of 9	ENSP00000496150.1	P10635-1
CYP2D6	ENST00000359033.4	TSL:1	c.353-89G>A		intron	N/A	ENSP00000351927.4	P10635-2
CYP2D6	ENST00000360124.10	TSL:1	n.353-89G>A		intron	N/A	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes

AF:

0.000370

AC:

AN:

151460

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0109

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00103

AC:

247

AN:

239014

AF XY:

0.000938

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000595

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0134

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000186

Gnomad OTH exome

AF:

0.000342

GnomAD4 exome

AF:

0.000246

AC:

358

AN:

1454632

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

169

AN XY:

723172

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33168

American (AMR)

AF:

0.0000454

AC:

AN:

44034

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26002

East Asian (EAS)

AF:

0.00799

AC:

315

AN:

39416

South Asian (SAS)

AF:

0.0000705

AC:

AN:

85158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52918

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1108228

Other (OTH)

AF:

0.000350

AC:

AN:

60046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000369

AC:

AN:

151574

Hom.:

Cov.:

AF XY:

0.000392

AC XY:

AN XY:

74066

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41184

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0109

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67824

Other (OTH)

AF:

0.00

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.0000728

Hom.:

ExAC

AF:

0.000952

AC:

115

ClinVar

ClinVar submissions

Significance:Likely benign; other

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

Eigen

Benign

0.091

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.33

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

3.2

PhyloP100

-0.15

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-6.4

REVEL

Uncertain

0.46

Sift

Uncertain

0.019

Sift4G

Uncertain

0.031

Vest4

0.31

MutPred

0.80

Gain of solvent accessibility (P = 0.0037)

MVP

0.80

MPC

0.46

ClinPred

0.19

GERP RS

2.4

Varity_R

0.40

gMVP

0.71

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

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