rs730882251

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_000106.6(CYP2D6):c.1321C>T(p.Arg441Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,549,788 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: 2.34

Publications

11 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: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.897

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.1321C>T	p.Arg441Cys	missense_variant	Exon 9 of 9	ENST00000645361.2	NP_000097.3	P10635-1C1ID52Q5Y7H2
CYP2D6	NM_001025161.3 link	c.1168C>T	p.Arg390Cys	missense_variant	Exon 8 of 8		NP_001020332.2	P10635-2Q5Y7H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2 link	c.1321C>T	p.Arg441Cys	missense_variant	Exon 9 of 9		NM_000106.6	ENSP00000496150.1		P10635-1

Frequencies

GnomAD3 genomes

AF:

0.000160

AC:

AN:

150230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000494

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000463

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000104

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000185

AC:

AN:

146298

AF XY:

0.000180

show subpopulations

Gnomad AFR exome

AF:

0.000136

Gnomad AMR exome

AF:

0.000170

Gnomad ASJ exome

AF:

0.00175

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000667

Gnomad NFE exome

AF:

0.0000905

Gnomad OTH exome

AF:

0.000484

GnomAD4 exome

AF:

0.000116

AC:

163

AN:

1399558

Hom.:

Cov.:

AF XY:

0.0000985

AC XY:

AN XY:

690584

show subpopulations

African (AFR)

AF:

0.000126

AC:

AN:

31728

American (AMR)

AF:

0.0000558

AC:

AN:

35826

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

25168

East Asian (EAS)

AF:

0.00

AC:

AN:

36114

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79314

European-Finnish (FIN)

AF:

0.0000404

AC:

AN:

49452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4554

European-Non Finnish (NFE)

AF:

0.000103

AC:

111

AN:

1079458

Other (OTH)

AF:

0.000224

AC:

AN:

57944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000160

AC:

AN:

150230

Hom.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

73328

show subpopulations

African (AFR)

AF:

0.0000494

AC:

AN:

40462

American (AMR)

AF:

0.000463

AC:

AN:

15120

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5082

South Asian (SAS)

AF:

0.00

AC:

AN:

4718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000104

AC:

AN:

67532

Other (OTH)

AF:

0.00

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000391

Hom.:

ExAC

AF:

0.0000630

AC:

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Other:1

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;T;T;T;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

.;.;D;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

4.1

H;H;H;.;.

PhyloP100

2.3

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.0

.;.;D;.;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

.;.;D;.;D

Sift4G

Pathogenic

0.0

.;.;D;D;D

Vest4

0.95, 0.90, 0.92

MVP

0.91

MPC

0.59

ClinPred

0.90

GERP RS

2.7

Varity_R

0.81

gMVP

0.76

Mutation Taster

=5/95

disease causing

(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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rs730882251

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