22-42127803-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Likely benign; drug response; other criteria provided, multiple submitters, no conflicts B:1 O:4
• Conservation: PhyloP100: -0.879

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]

NDUFA6-DT (HGNC:45273): (NDUFA6 divergent transcript)

ACMG classification

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	UniProt
CYP2D6	NM_000106.6	c.985+39G>A		intron_variant		ENST00000645361.2
CYP2D6	NM_001025161.3	c.832+39G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2	c.985+39G>A		intron_variant			NM_000106.6	P1
NDUFA6-DT	ENST00000439129.5	n.1718+2396C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0697 AC: 10540 AN: 151116 Hom.: 778 Cov.: 32

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

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.: 34 AF XY: 0.0960 AC XY: 69497 AN XY: 724264

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.: 32 AF XY: 0.0679 AC XY: 5015 AN XY: 73910

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:1 Other:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 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).
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. -

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	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.7
Dann	Benign	0.66
DEOGEN2	Benign	0.0081	T
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0016	T
MutationTaster	Benign	1.0	N;N;N
Sift4G	Benign	0.42	T
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

Other links and lift over

dbSNP: rs28371725; hg19: chr22-42523805; COSMIC: COSV62244295; COSMIC: COSV62244295;