22-42127803-C-T

Position:

chr22-42127803-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000106.6(CYP2D6):c.985+39G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0917 in 1,606,516 control chromosomes in the GnomAD database, including 11,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,drug response,other (★★).

Frequency

Genomes: 𝑓 0.070 ( 775 hom., cov: 32)

Exomes 𝑓: 0.094 ( 10990 hom. )

Consequence

CYP2D6
NM_000106.6 intron

Scores

Clinical Significance

Likely benign; drug response; other criteria provided, multiple submitters, no conflicts B:1O:4

Conservation

PhyloP100: -0.879

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:):

NDUFA6-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015609562).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6 linkuse as main transcript	c.985+39G>A		intron_variant		ENST00000645361.2	NP_000097.3	P10635-1C1ID52Q5Y7H2
CYP2D6	NM_001025161.3 linkuse as main transcript	c.832+39G>A		intron_variant			NP_001020332.2	P10635-2Q5Y7H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2 linkuse as main transcript	c.985+39G>A		intron_variant			NM_000106.6	ENSP00000496150.1		P10635-1

Frequencies

GnomAD3 genomes

AF:

0.0697

AC:

10540

AN:

151116

Hom.:

778

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0260

Gnomad AMI

AF:

0.0773

Gnomad AMR

AF:

0.0662

Gnomad ASJ

AF:

0.179

Gnomad EAS

AF:

0.0330

Gnomad SAS

AF:

0.126

Gnomad FIN

AF:

0.0301

Gnomad MID

AF:

0.143

Gnomad NFE

AF:

0.0955

Gnomad OTH

AF:

0.0841

GnomAD3 exomes

AF:

0.0807

AC:

20150

AN:

249596

Hom.:

1590

AF XY:

0.0864

AC XY:

11692

AN XY:

135262

show subpopulations

Gnomad AFR exome

AF:

0.0276

Gnomad AMR exome

AF:

0.0399

Gnomad ASJ exome

AF:

0.176

Gnomad EAS exome

AF:

0.0321

Gnomad SAS exome

AF:

0.135

Gnomad FIN exome

AF:

0.0320

Gnomad NFE exome

AF:

0.0938

Gnomad OTH exome

AF:

0.0962

GnomAD4 exome

AF:

0.0939

AC:

136709

AN:

1455284

Hom.:

10990

Cov.:

AF XY:

0.0960

AC XY:

69497

AN XY:

724264

show subpopulations

Gnomad4 AFR exome

AF:

0.0262

Gnomad4 AMR exome

AF:

0.0444

Gnomad4 ASJ exome

AF:

0.179

Gnomad4 EAS exome

AF:

0.0214

Gnomad4 SAS exome

AF:

0.136

Gnomad4 FIN exome

AF:

0.0323

Gnomad4 NFE exome

AF:

0.0975

Gnomad4 OTH exome

AF:

0.103

GnomAD4 genome

AF:

0.0697

AC:

10534

AN:

151232

Hom.:

775

Cov.:

AF XY:

0.0679

AC XY:

5015

AN XY:

73910

show subpopulations

Gnomad4 AFR

AF:

0.0260

Gnomad4 AMR

AF:

0.0662

Gnomad4 ASJ

AF:

0.179

Gnomad4 EAS

AF:

0.0321

Gnomad4 SAS

AF:

0.126

Gnomad4 FIN

AF:

0.0301

Gnomad4 NFE

AF:

0.0955

Gnomad4 OTH

AF:

0.0833

Alfa

AF:

0.0911

Hom.:

287

Bravo

AF:

0.0703

TwinsUK

AF:

0.0947

AC:

351

ALSPAC

AF:

0.0996

AC:

384

ESP6500AA

AF:

0.0337

AC:

148

ESP6500EA

AF:

0.100

AC:

859

ExAC

AF:

0.0806

AC:

9777

Asia WGS

AF:

0.0780

AC:

270

AN:

3466

ClinVar

Significance: Likely benign; drug response; other

Submissions summary: Benign:1Other:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2018	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. -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 06, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Tamoxifen response

Other:1

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

May 01, 2019

CYP2D6*41 has decreased function: individuals with one decreased function and one no function allele ( e.g., *4/*41) are intermediate metabolizers; individuals with two decreased function alleles (e.g. *41/*41) are normal metabolizers or intermediate metabolizers (controversy remains). Therapeutic recommendations from professional societies state that intermediate metabolizers may benefit less from tamoxifen therapy because they have lower concentrations of tamoxifen's major active metabolite, endoxifin, compared with normal metabolizers. Individuals with one decreased function and one no function allele (e.g. *4/*41) are intermediate metabolizers. Individuals with two decreased function alleles (e.g. *41/*41) are normal metabolizers or intermediate metabolizers (controversy remains).

Tramadol response

Other:1

drug response, no assertion criteria provided

research

Bruce Budowle Laboratory, University of North Texas Health Science Center

Apr 28, 2018

- T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1

Deutetrabenazine response

Other:1

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

May 01, 2019

CYP2D6*41 has decreased function: individuals with one decreased function and one no function allele ( e.g., *4/*41) are intermediate metabolizers; individuals with two decreased function alleles (e.g. *41/*41) are normal metabolizers or intermediate metabolizers (controversy remains). Therapeutic recommendations from professional societies state that the maximum dose of deutetrabenazine should not exceed 36 mg per day in individuals with 2 decreased function alleles (CYP2D6 poor metabolizers) to avoid abnormally high plasma levels due to reduced metabolic clearance. Individuals with one decreased function and one no function allele ( e.g., *4/*41) are intermediate metabolizers. Individuals with two decreased function alleles (e.g. *41/*41) are normal metabolizers or intermediate metabolizers (controversy remains).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.7

DANN

Benign

0.66

DEOGEN2

Benign

0.0081

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.18

MetaRNN

Benign

0.0016

Sift4G

Benign

0.42

Vest4

0.18

GERP RS

0.50

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over