chr22-42128945-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

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:1O:5

Conservation

PhyloP100: 5.88

Publications

528 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 -16 ACMG points.

BP6

Variant 22-42128945-C-T is Benign according to our data. Variant chr22-42128945-C-T is described in ClinVar as Likely_benign|drug_response|other. ClinVar VariationId is 16889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000106.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	NM_000106.6	MANE Select	c.506-1G>A		splice_acceptor intron	N/A	NP_000097.3
	CYP2D6	NM_001025161.3		c.353-1G>A		splice_acceptor intron	N/A	NP_001020332.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CYP2D6	ENST00000645361.2	MANE Select	c.506-1G>A	splice_acceptor intron	N/A	ENSP00000496150.1
CYP2D6	ENST00000359033.4	TSL:1	c.353-1G>A	splice_acceptor intron	N/A	ENSP00000351927.4
CYP2D6	ENST00000360124.10	TSL:1	n.353-1G>A	splice_acceptor intron	N/A	ENSP00000353241.6

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21187

AN:

150074

Hom.:

1924

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.139

AC:

24767

AN:

178714

AF XY:

0.138

show subpopulations

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 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.:

AF XY:

0.164

AC XY:

115855

AN XY:

707972

show subpopulations

African (AFR)

AF:

0.0705

AC:

2301

AN:

32650

American (AMR)

AF:

0.112

AC:

4423

AN:

39646

Ashkenazi Jewish (ASJ)

AF:

0.176

AC:

4482

AN:

25532

East Asian (EAS)

AF:

0.00257

AC:

AN:

38474

South Asian (SAS)

AF:

0.100

AC:

8299

AN:

82608

European-Finnish (FIN)

AF:

0.102

AC:

5266

AN:

51448

Middle Eastern (MID)

AF:

0.0983

AC:

559

AN:

5684

European-Non Finnish (NFE)

AF:

0.185

AC:

201817

AN:

1092906

Other (OTH)

AF:

0.148

AC:

8762

AN:

59062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.414

Heterozygous variant carriers

8553

17107

25660

34214

42767

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7416

14832

22248

29664

37080

<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:

0.141

AC:

21179

AN:

150188

Hom.:

1924

Cov.:

AF XY:

0.134

AC XY:

9833

AN XY:

73364

show subpopulations

African (AFR)

AF:

0.0766

AC:

3114

AN:

40660

American (AMR)

AF:

0.131

AC:

1982

AN:

15166

Ashkenazi Jewish (ASJ)

AF:

0.184

AC:

633

AN:

3434

East Asian (EAS)

AF:

0.00660

AC:

AN:

5152

South Asian (SAS)

AF:

0.107

AC:

511

AN:

4758

European-Finnish (FIN)

AF:

0.0969

AC:

1023

AN:

10562

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.199

AC:

13343

AN:

67176

Other (OTH)

AF:

0.141

AC:

295

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

756

1513

2269

3026

3782

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

230

460

690

920

1150

<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:

0.176

Hom.:

1235

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

ClinVar submissions as Germline

Significance:Likely benign; drug response; other

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Debrisoquine, poor metabolism of (1)

Deutetrabenazine response (1)

not provided (1)

Tamoxifen response (1)

Tramadol response (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.94

PhyloP100

5.9

GERP RS

3.4

Mutation Taster

=63/37

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over