22-42128945-C-T

Variant names:

• chr22-42128945-C-T
• rs3892097
• NM_000106.6:c.506-1G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BA1

The NM_000106.6(CYP2D6):​c.506-1G>A variant causes a splice acceptor, intron 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, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign; drug response; other criteria provided, multiple submitters, no conflicts B:1 O:5
• Conservation: PhyloP100: 5.88

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 -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 rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.506-1G>A		splice_acceptor_variant, intron_variant	Intron 3 of 8	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.353-1G>A		splice_acceptor_variant, 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	c.506-1G>A		splice_acceptor_variant, intron_variant	Intron 3 of 8		NM_000106.6	ENSP00000496150.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21187 AN: 150074 Hom.: 1924 Cov.: 32

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

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.: 79 AF XY: 0.164 AC XY: 115855 AN XY: 707972

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.: 32 AF XY: 0.134 AC XY: 9833 AN XY: 73364

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:1 Other:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 09, 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. *4/*41) are intermediate metabolizers. Individuals with 2 no function alleles (e.g. *4/*4) are poor metabolizers.

Tramadol response Other:1

Apr 28, 2018

Bruce Budowle Laboratory, University of North Texas Health Science Center

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

- 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

May 18, 2015

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., *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

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).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
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

Other links and lift over

dbSNP: rs3892097; hg19: chr22-42524947; COSMIC: COSV62243440; COSMIC: COSV62243440;