rs35742686

Positions:

chr22-42128241-CT-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1BS2

The NM_000106.6(CYP2D6):c.775delA(p.Arg259fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,610,668 control chromosomes in the GnomAD database, including 957 homozygotes. Variant has been reported in ClinVar as Likely benign,other (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.012 ( 63 hom., cov: 31)

Exomes 𝑓: 0.015 ( 894 hom. )

Consequence

CYP2D6
NM_000106.6 frameshift

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 0.218

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 -8 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0123 (1854/151158) while in subpopulation NFE AF= 0.017 (1150/67728). AF 95% confidence interval is 0.0162. There are 63 homozygotes in gnomad4. There are 929 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1854 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.775delA	p.Arg259fs	frameshift_variant	5/9	ENST00000645361.2	NP_000097.3	P10635-1C1ID52Q5Y7H2
CYP2D6	NM_001025161.3 link	c.622delA	p.Arg208fs	frameshift_variant	4/8		NP_001020332.2	P10635-2Q5Y7H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2 link	c.775delA	p.Arg259fs	frameshift_variant	5/9		NM_000106.6	ENSP00000496150.1		P10635-1

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1854

AN:

151044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00321

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00856

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00167

Gnomad FIN

AF:

0.0361

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0170

Gnomad OTH

AF:

0.0126

GnomAD3 exomes

AF:

0.0122

AC:

3049

AN:

249674

Hom.:

100

AF XY:

0.0120

AC XY:

1626

AN XY:

134986

show subpopulations

Gnomad AFR exome

AF:

0.00207

Gnomad AMR exome

AF:

0.00476

Gnomad ASJ exome

AF:

0.00368

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00148

Gnomad FIN exome

AF:

0.0354

Gnomad NFE exome

AF:

0.0172

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.0155

AC:

22551

AN:

1459510

Hom.:

894

Cov.:

AF XY:

0.0149

AC XY:

10840

AN XY:

726018

show subpopulations

Gnomad4 AFR exome

AF:

0.00231

Gnomad4 AMR exome

AF:

0.00493

Gnomad4 ASJ exome

AF:

0.00471

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00178

Gnomad4 FIN exome

AF:

0.0338

Gnomad4 NFE exome

AF:

0.0175

Gnomad4 OTH exome

AF:

0.0114

GnomAD4 genome

AF:

0.0123

AC:

1854

AN:

151158

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

929

AN XY:

73878

show subpopulations

Gnomad4 AFR

AF:

0.00320

Gnomad4 AMR

AF:

0.00855

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00167

Gnomad4 FIN

AF:

0.0361

Gnomad4 NFE

AF:

0.0170

Gnomad4 OTH

AF:

0.0124

Alfa

AF:

0.0114

Hom.:

Bravo

AF:

0.00999

Asia WGS

AF:

0.00348

AC:

AN:

3466

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

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. -

Debrisoquine, poor metabolism of

Other:1

drug response, no assertion criteria provided

literature only

OMIM

Jun 01, 1997

- -

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