rs5030656

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PM4_SupportingBS1BS2

The NM_000106.6(CYP2D6):c.841_843del(p.Lys281del) variant causes a inframe deletion, splice region change. The variant allele was found at a frequency of 0.0249 in 1,604,474 control chromosomes in the GnomAD database, including 1,878 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign,other (★★).

Frequency

Genomes: 𝑓 0.018 ( 132 hom., cov: 31)

Exomes 𝑓: 0.026 ( 1746 hom. )

Consequence

CYP2D6
NM_000106.6 inframe_deletion, splice_region

Scores

Not classified

Clinical Significance

Likely benign; other criteria provided, multiple submitters, no conflicts B:1O:2

Conservation

PhyloP100: 4.46

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.

PM4

Nonframeshift variant in NON repetitive region in NM_000106.6. Strenght limited to Supporting due to length of the change: 1aa.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0177 (2664/150750) while in subpopulation NFE AF= 0.0285 (1924/67614). AF 95% confidence interval is 0.0274. There are 132 homozygotes in gnomad4. There are 1242 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2664 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6 linkuse as main transcript	c.841_843del	p.Lys281del	inframe_deletion, splice_region_variant	5/9	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3 linkuse as main transcript	c.688_690del	p.Lys230del	inframe_deletion, splice_region_variant	4/8		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2 linkuse as main transcript	c.841_843del	p.Lys281del	inframe_deletion, splice_region_variant	5/9		NM_000106.6	ENSP00000496150	P1	P10635-1
NDUFA6-DT	ENST00000439129.5 linkuse as main transcript	n.1718+2769_1718+2771del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0177

AC:

2666

AN:

150638

Hom.:

132

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00549

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0206

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000631

Gnomad FIN

AF:

0.0146

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0285

Gnomad OTH

AF:

0.0184

GnomAD3 exomes

AF:

0.0154

AC:

3675

AN:

238732

Hom.:

137

AF XY:

0.0152

AC XY:

1963

AN XY:

129004

show subpopulations

Gnomad AFR exome

AF:

0.00338

Gnomad AMR exome

AF:

0.0123

Gnomad ASJ exome

AF:

0.00315

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00212

Gnomad FIN exome

AF:

0.0129

Gnomad NFE exome

AF:

0.0258

Gnomad OTH exome

AF:

0.0177

GnomAD4 exome

AF:

0.0256

AC:

37232

AN:

1453724

Hom.:

1746

AF XY:

0.0249

AC XY:

17975

AN XY:

722536

show subpopulations

Gnomad4 AFR exome

AF:

0.00377

Gnomad4 AMR exome

AF:

0.0139

Gnomad4 ASJ exome

AF:

0.00327

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00266

Gnomad4 FIN exome

AF:

0.0135

Gnomad4 NFE exome

AF:

0.0308

Gnomad4 OTH exome

AF:

0.0227

GnomAD4 genome

AF:

0.0177

AC:

2664

AN:

150750

Hom.:

132

Cov.:

AF XY:

0.0169

AC XY:

1242

AN XY:

73646

show subpopulations

Gnomad4 AFR

AF:

0.00548

Gnomad4 AMR

AF:

0.0204

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000631

Gnomad4 FIN

AF:

0.0146

Gnomad4 NFE

AF:

0.0285

Gnomad4 OTH

AF:

0.0183

Alfa

AF:

0.0188

Hom.:

Bravo

AF:

0.0175

Asia WGS

AF:

0.00116

AC:

AN:

3464

ClinVar

Significance: Likely benign; other

Submissions summary: Benign:1Other:2

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).

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DG_spliceai

1.0

Position offset: 4

DS_DL_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