chr22-42128945-C-T

Position:

chr22-42128945-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BA1

The NM_000106.6(CYP2D6):c.506-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.163 in 1,578,198 control chromosomes in the GnomAD database, including 9,043 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign,drug response,other (★★).

Frequency

Genomes: 𝑓 0.14 ( 1924 hom., cov: 32)

Exomes 𝑓: 0.17 ( 7119 hom. )

Consequence

CYP2D6
NM_000106.6 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely benign; drug response; other criteria provided, multiple submitters, no conflicts B:1O:5

Conservation

PhyloP100: 5.88

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 made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 5: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, MutationTaster was below the threshold]

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.196 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.506-1G>A		splice_acceptor_variant		ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3 linkuse as main transcript	c.353-1G>A		splice_acceptor_variant			NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2 linkuse as main transcript	c.506-1G>A		splice_acceptor_variant			NM_000106.6	ENSP00000496150	P1	P10635-1
NDUFA6-DT	ENST00000439129.5 linkuse as main transcript	n.1718+3538C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21187

AN:

150074

Hom.:

1924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0768

Gnomad AMI

AF:

0.238

Gnomad AMR

AF:

0.131

Gnomad ASJ

AF:

0.184

Gnomad EAS

AF:

0.00678

Gnomad SAS

AF:

0.108

Gnomad FIN

AF:

0.0969

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.199

Gnomad OTH

AF:

0.144

GnomAD3 exomes

AF:

0.139

AC:

24767

AN:

178714

Hom.:

2273

AF XY:

0.138

AC XY:

13202

AN XY:

95348

show subpopulations

Gnomad AFR exome

AF:

0.0840

Gnomad AMR exome

AF:

0.111

Gnomad ASJ exome

AF:

0.180

Gnomad EAS exome

AF:

0.00309

Gnomad SAS exome

AF:

0.104

Gnomad FIN exome

AF:

0.0990

Gnomad NFE exome

AF:

0.197

Gnomad OTH exome

AF:

0.155

GnomAD4 exome

AF:

0.165

AC:

236008

AN:

1428010

Hom.:

7119

Cov.:

AF XY:

0.164

AC XY:

115855

AN XY:

707972

show subpopulations

Gnomad4 AFR exome

AF:

0.0705

Gnomad4 AMR exome

AF:

0.112

Gnomad4 ASJ exome

AF:

0.176

Gnomad4 EAS exome

AF:

0.00257

Gnomad4 SAS exome

AF:

0.100

Gnomad4 FIN exome

AF:

0.102

Gnomad4 NFE exome

AF:

0.185

Gnomad4 OTH exome

AF:

0.148

GnomAD4 genome

AF:

0.141

AC:

21179

AN:

150188

Hom.:

1924

Cov.:

AF XY:

0.134

AC XY:

9833

AN XY:

73364

show subpopulations

Gnomad4 AFR

AF:

0.0766

Gnomad4 AMR

AF:

0.131

Gnomad4 ASJ

AF:

0.184

Gnomad4 EAS

AF:

0.00660

Gnomad4 SAS

AF:

0.107

Gnomad4 FIN

AF:

0.0969

Gnomad4 NFE

AF:

0.199

Gnomad4 OTH

AF:

0.141

Alfa

AF:

0.177

Hom.:

1231

Bravo

AF:

0.143

TwinsUK

AF:

0.207

AC:

766

ALSPAC

AF:

0.211

AC:

814

ESP6500AA

AF:

0.0729

AC:

314

ESP6500EA

AF:

0.191

AC:

1620

ExAC

AF:

0.110

AC:

12844

Asia WGS

AF:

0.0690

AC:

244

AN:

3468

ClinVar

Significance: Likely benign; drug response; other

Submissions summary: Benign:1Other:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 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. -

Tamoxifen response

Other:1

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

May 01, 2019

Individuals who do not have any fully functional alleles are either intermediate metabolizers (one decreased function and one no function allele, e.g., *4/*41) or poor metabolizers (2 no function alleles, e.g., *4/*4). Currently, there is no consensus on therapeutic guidelines for tamoxifen based on CYP2D6 genotype. Professional societies suggest that poor 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 2 no function alleles (e.g. *4/*4) are poor metabolizers.

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

Debrisoquine, poor metabolism of

Other:1

drug response, no assertion criteria provided

literature only

OMIM

May 18, 2015

- -

Deutetrabenazine response

Other:1

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

May 01, 2019

Individuals who do not have any fully functional alleles are either intermediate metabolizers (one decreased function and one no function allele, e.g., *4/*41) or poor metabolizers (2 no function alleles, e.g., *4/*4).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 2 no function alleles (e.g., *4/*4) are poor metabolizers.

not provided

Other:1

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).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.94

MutationTaster

Benign

1.0e-37

P;P;P

GERP RS

3.4

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.97

Position offset: -2

DS_AL_spliceai

1.0

Position offset: -1

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