chr22-42129819-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000106.6(CYP2D6):c.271C>A(p.Leu91Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,535,588 control chromosomes in the GnomAD database, including 31,027 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

Frequency

Genomes: 𝑓 0.12 ( 1939 hom., cov: 30)

Exomes 𝑓: 0.15 ( 29088 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: 0.482

Publications

46 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003934562).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.271C>A	p.Leu91Met	missense_variant	Exon 2 of 9	ENST00000645361.2	NP_000097.3	P10635-1C1ID52Q5Y7H2
CYP2D6	NM_001025161.3 link	c.271C>A	p.Leu91Met	missense_variant	Exon 2 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.271C>A	p.Leu91Met	missense_variant	Exon 2 of 9		NM_000106.6	ENSP00000496150.1		P10635-1

Frequencies

GnomAD3 genomes

AF:

0.123

AC:

18464

AN:

150050

Hom.:

1938

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0377

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.101

Gnomad ASJ

AF:

0.186

Gnomad EAS

AF:

0.00291

Gnomad SAS

AF:

0.0862

Gnomad FIN

AF:

0.0929

Gnomad MID

AF:

0.0924

Gnomad NFE

AF:

0.192

Gnomad OTH

AF:

0.123

GnomAD2 exomes

AF:

0.0926

AC:

20371

AN:

219934

AF XY:

0.0943

show subpopulations

Gnomad AFR exome

AF:

0.0258

Gnomad AMR exome

AF:

0.0585

Gnomad ASJ exome

AF:

0.125

Gnomad EAS exome

AF:

0.000684

Gnomad FIN exome

AF:

0.0537

Gnomad NFE exome

AF:

0.145

Gnomad OTH exome

AF:

0.107

GnomAD4 exome

AF:

0.153

AC:

211871

AN:

1385428

Hom.:

29088

Cov.:

AF XY:

0.151

AC XY:

104369

AN XY:

690374

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0293

AC:

968

AN:

32986

American (AMR)

AF:

0.0690

AC:

3000

AN:

43484

Ashkenazi Jewish (ASJ)

AF:

0.169

AC:

4175

AN:

24760

East Asian (EAS)

AF:

0.000556

AC:

AN:

39546

South Asian (SAS)

AF:

0.0824

AC:

6944

AN:

84224

European-Finnish (FIN)

AF:

0.0890

AC:

4375

AN:

49130

Middle Eastern (MID)

AF:

0.0915

AC:

512

AN:

5598

European-Non Finnish (NFE)

AF:

0.176

AC:

184202

AN:

1047690

Other (OTH)

AF:

0.132

AC:

7673

AN:

58010

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.322

Heterozygous variant carriers

9293

18585

27878

37170

46463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5574

11148

16722

22296

27870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.123

AC:

18458

AN:

150160

Hom.:

1939

Cov.:

AF XY:

0.116

AC XY:

8484

AN XY:

73324

show subpopulations

African (AFR)

AF:

0.0376

AC:

1537

AN:

40852

American (AMR)

AF:

0.101

AC:

1520

AN:

15034

Ashkenazi Jewish (ASJ)

AF:

0.186

AC:

638

AN:

3434

East Asian (EAS)

AF:

0.00273

AC:

AN:

5134

South Asian (SAS)

AF:

0.0854

AC:

406

AN:

4754

European-Finnish (FIN)

AF:

0.0929

AC:

980

AN:

10548

Middle Eastern (MID)

AF:

0.0959

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.192

AC:

12886

AN:

67176

Other (OTH)

AF:

0.122

AC:

252

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

665

1330

1995

2660

3325

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

200

400

600

800

1000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.152

Hom.:

446

Bravo

AF:

0.122

ExAC

AF:

0.109

AC:

12975

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0063

T;T;T;T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.58

.;.;T;T;T

MetaRNN

Benign

0.0039

T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Pathogenic

3.4

M;M;M;.;M

PhyloP100

0.48

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.7

.;.;N;.;N

REVEL

Uncertain

0.47

Sift

Benign

0.039

.;.;D;.;D

Sift4G

Uncertain

0.035

.;.;D;D;D

Vest4

0.15, 0.23, 0.25

MPC

0.52

ClinPred

0.093

GERP RS

2.4

Varity_R

0.12

gMVP

0.63

Mutation Taster

=94/6

polymorphism (auto)

(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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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