rs5030655

Positions:

chr22-42129083-CA-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000106.6(CYP2D6):c.454delT(p.Trp152fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,609,822 control chromosomes in the GnomAD database, including 641 homozygotes. Variant has been reported in ClinVar as Likely benign,drug response,other (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0085 ( 39 hom., cov: 32)

Exomes 𝑓: 0.011 ( 602 hom. )

Consequence

CYP2D6
NM_000106.6 frameshift

Scores

Not classified

Clinical Significance

Benign/Likely benign; drug response; other criteria provided, multiple submitters, no conflicts B:2O:4

Conservation

PhyloP100: -0.00600

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 Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 1292 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.454delT	p.Trp152fs	frameshift_variant	3/9	ENST00000645361.2	NP_000097.3	P10635-1C1ID52Q5Y7H2
CYP2D6	NM_001025161.3 link	c.353-140delT		intron_variant			NP_001020332.2	P10635-2Q5Y7H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2 link	c.454delT	p.Trp152fs	frameshift_variant	3/9		NM_000106.6	ENSP00000496150.1		P10635-1

Frequencies

GnomAD3 genomes

AF:

0.00852

AC:

1292

AN:

151570

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00538

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0246

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.00530

GnomAD3 exomes

AF:

0.00792

AC:

1935

AN:

244380

Hom.:

AF XY:

0.00812

AC XY:

1081

AN XY:

133196

show subpopulations

Gnomad AFR exome

AF:

0.00212

Gnomad AMR exome

AF:

0.00369

Gnomad ASJ exome

AF:

0.00836

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00165

Gnomad FIN exome

AF:

0.0216

Gnomad NFE exome

AF:

0.0104

Gnomad OTH exome

AF:

0.00591

GnomAD4 exome

AF:

0.0110

AC:

16105

AN:

1458138

Hom.:

602

Cov.:

AF XY:

0.0107

AC XY:

7787

AN XY:

725324

show subpopulations

Gnomad4 AFR exome

AF:

0.00195

Gnomad4 AMR exome

AF:

0.00440

Gnomad4 ASJ exome

AF:

0.0107

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00208

Gnomad4 FIN exome

AF:

0.0191

Gnomad4 NFE exome

AF:

0.0125

Gnomad4 OTH exome

AF:

0.00861

GnomAD4 genome

AF:

0.00852

AC:

1292

AN:

151684

Hom.:

Cov.:

AF XY:

0.00890

AC XY:

660

AN XY:

74152

show subpopulations

Gnomad4 AFR

AF:

0.00228

Gnomad4 AMR

AF:

0.00537

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00146

Gnomad4 FIN

AF:

0.0246

Gnomad4 NFE

AF:

0.0117

Gnomad4 OTH

AF:

0.00525

Alfa

AF:

0.00177

Hom.:

Bravo

AF:

0.00711

ClinVar

Significance: Benign/Likely benign; drug response; other

Submissions summary: Benign:2Other:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other: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).
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 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. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CYP2D6: BS1, BS2 -

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. *6/*41) are intermediate metabolizers. Individuals with 2 no function alleles (e.g. *6/*6) are poor metabolizers.

Debrisoquine, poor metabolism of

Other:1

drug response, no assertion criteria provided

literature only

OMIM

Jun 01, 1994

- -

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., *6/*41) or poor metabolizers (2 no function alleles, e.g., *6/*6). 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., *6/*41) are intermediate metabolizers. Individuals with 2 no function alleles (e.g., *6/*6) are poor metabolizers.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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