rs5030655

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_000106.6(CYP2D6):c.454delT(p.Trp152GlyfsTer2) 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

Publications

179 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 -12 ACMG points.

BP6

Variant 22-42129083-CA-C is Benign according to our data. Variant chr22-42129083-CA-C is described in ClinVar as Benign/Likely_benign|drug_response|other. ClinVar VariationId is 16891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1292 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.454delT	p.Trp152GlyfsTer2	frameshift_variant	Exon 3 of 9	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3 link	c.353-140delT		intron_variant	Intron 2 of 7		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2 link	c.454delT	p.Trp152GlyfsTer2	frameshift_variant	Exon 3 of 9		NM_000106.6	ENSP00000496150.1

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

GnomAD2 exomes

AF:

0.00792

AC:

1935

AN:

244380

AF XY:

0.00812

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 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

African (AFR)

AF:

0.00195

AC:

AN:

33318

American (AMR)

AF:

0.00440

AC:

196

AN:

44526

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

279

AN:

26082

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39554

South Asian (SAS)

AF:

0.00208

AC:

179

AN:

85942

European-Finnish (FIN)

AF:

0.0191

AC:

1011

AN:

52994

Middle Eastern (MID)

AF:

0.00505

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0125

AC:

13827

AN:

1109820

Other (OTH)

AF:

0.00861

AC:

518

AN:

60160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

951

1902

2852

3803

4754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

490

980

1470

1960

2450

<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:

0.00852

AC:

1292

AN:

151684

Hom.:

Cov.:

AF XY:

0.00890

AC XY:

660

AN XY:

74152

show subpopulations

African (AFR)

AF:

0.00228

AC:

AN:

41230

American (AMR)

AF:

0.00537

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00146

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.0246

AC:

261

AN:

10620

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0117

AC:

794

AN:

67850

Other (OTH)

AF:

0.00525

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

116

174

232

290

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:

0.00177

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

Aug 06, 2018

Eurofins Ntd Llc (ga)

Significance:other

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CYP2D6: BS1, BS2 -

Mar 14, 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. -

Tamoxifen response

Other:1

May 01, 2019

Medical Genetics Summaries

Significance:drug response

Review Status:criteria provided, single submitter

Collection Method:curation

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

Jun 01, 1994

OMIM

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Deutetrabenazine response

Other:1

May 01, 2019

Medical Genetics Summaries

Significance:drug response

Review Status:criteria provided, single submitter

Collection Method:curation

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

PhyloP100

-0.0060

Mutation Taster

=137/63

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