dbSNP rs267608295: CYP2D6:p.Arg343Trp (chr22-42127593-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000106.6(CYP2D6):c.1027C>T(p.Arg343Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,611,916 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.481

Publications

4 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 -4 ACMG points.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.1027C>T	p.Arg343Trp	missense_variant	Exon 7 of 9	ENST00000645361.2	NP_000097.3	P10635-1C1ID52Q5Y7H2
CYP2D6	NM_001025161.3 link	c.874C>T	p.Arg292Trp	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.1027C>T	p.Arg343Trp	missense_variant	Exon 7 of 9		NM_000106.6	ENSP00000496150.1		P10635-1

Frequencies

GnomAD3 genomes

AF:

0.0000396

AC:

AN:

151662

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000834

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000638

AC:

AN:

250948

AF XY:

0.0000811

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000288

AC:

AN:

1460140

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726366

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33392

American (AMR)

AF:

0.0000224

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.000255

AC:

AN:

86132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1110718

Other (OTH)

AF:

0.0000829

AC:

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000395

AC:

AN:

151776

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41296

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000834

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67868

Other (OTH)

AF:

0.00

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000356

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

T;T;T;T;.

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.011

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.89

.;.;D;D;D

M_CAP

Uncertain

0.089

MetaRNN

Uncertain

0.70

D;D;D;D;D

MetaSVM

Uncertain

-0.0024

MutationAssessor

Pathogenic

4.0

H;H;H;.;.

PhyloP100

0.48

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-7.1

.;.;D;.;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0070

.;.;D;.;D

Sift4G

Uncertain

0.013

.;.;D;D;D

Vest4

0.63, 0.56, 0.61

MVP

0.81

MPC

0.37

ClinPred

0.95

GERP RS

2.6

Varity_R

0.21

gMVP

0.54

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

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