rs28371717

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000106.6(CYP2D6):c.709G>T(p.Ala237Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,610,552 control chromosomes in the GnomAD database, including 650 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 38 hom., cov: 31)

Exomes 𝑓: 0.011 ( 612 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.594

Publications

35 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048805773).

BP6

Variant 22-42128308-C-A is Benign according to our data. Variant chr22-42128308-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 513099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1198 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.709G>T	p.Ala237Ser	missense_variant	Exon 5 of 9	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3 link	c.556G>T	p.Ala186Ser	missense_variant	Exon 4 of 8		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2 link	c.709G>T	p.Ala237Ser	missense_variant	Exon 5 of 9		NM_000106.6	ENSP00000496150.1

Frequencies

GnomAD3 genomes

AF:

0.00794

AC:

1198

AN:

150866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00172

Gnomad AMI

AF:

0.00111

Gnomad AMR

AF:

0.00448

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00421

Gnomad FIN

AF:

0.00945

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0129

Gnomad OTH

AF:

0.00726

GnomAD2 exomes

AF:

0.00791

AC:

1984

AN:

250760

AF XY:

0.00805

show subpopulations

Gnomad AFR exome

AF:

0.00210

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0104

Gnomad NFE exome

AF:

0.0117

Gnomad OTH exome

AF:

0.00686

GnomAD4 exome

AF:

0.0106

AC:

15514

AN:

1459572

Hom.:

612

Cov.:

AF XY:

0.0105

AC XY:

7600

AN XY:

726086

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

33342

American (AMR)

AF:

0.00168

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

309

AN:

26128

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39602

South Asian (SAS)

AF:

0.00628

AC:

541

AN:

86120

European-Finnish (FIN)

AF:

0.0116

AC:

622

AN:

53400

Middle Eastern (MID)

AF:

0.00851

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0121

AC:

13406

AN:

1110282

Other (OTH)

AF:

0.00748

AC:

451

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

896

1792

2687

3583

4479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

470

940

1410

1880

2350

<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:

0.00793

AC:

1198

AN:

150980

Hom.:

Cov.:

AF XY:

0.00793

AC XY:

585

AN XY:

73778

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

40854

American (AMR)

AF:

0.00447

AC:

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00421

AC:

AN:

4746

European-Finnish (FIN)

AF:

0.00945

AC:

100

AN:

10578

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0129

AC:

873

AN:

67698

Other (OTH)

AF:

0.00718

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

115

173

230

288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0108

Hom.:

Bravo

AF:

0.00694

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0101

AC:

ExAC

AF:

0.00756

AC:

917

Asia WGS

AF:

0.000289

AC:

AN:

3468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3Other: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

- -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CYP2D6: BP4, BS1, BS2 -

not specified

Benign:1

Mar 09, 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

0.12

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.41

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0044

T;T;T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.39

.;.;T;T;T

MetaRNN

Benign

0.0049

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.3

L;L;L;.;.

PhyloP100

-0.59

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.4

.;.;N;.;N

REVEL

Benign

0.063

Sift

Benign

0.41

.;.;T;.;T

Sift4G

Benign

0.41

.;.;T;T;T

Vest4

0.19, 0.22, 0.22

MVP

0.54

MPC

0.11

ClinPred

0.012

GERP RS

-6.5

Varity_R

0.16

gMVP

0.46

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over