22-42126749-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000106.6(CYP2D6):c.1319G>A(p.Arg440His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,549,504 control chromosomes in the GnomAD database, including 5 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 0.00039 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00014 ( 5 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: 0.319

Publications

15 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06325573).

BS2

High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.1319G>A	p.Arg440His	missense_variant	Exon 9 of 9	ENST00000645361.2	NP_000097.3	P10635-1C1ID52Q5Y7H2
CYP2D6	NM_001025161.3 link	c.1166G>A	p.Arg389His	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.1319G>A	p.Arg440His	missense_variant	Exon 9 of 9		NM_000106.6	ENSP00000496150.1		P10635-1

Frequencies

GnomAD3 genomes

AF:

0.000387

AC:

AN:

150038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00225

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000193

Gnomad OTH

AF:

0.00196

GnomAD2 exomes

AF:

0.000219

AC:

AN:

145816

AF XY:

0.000270

show subpopulations

Gnomad AFR exome

AF:

0.000271

Gnomad AMR exome

AF:

0.000554

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000200

Gnomad NFE exome

AF:

0.000200

Gnomad OTH exome

AF:

0.000485

GnomAD4 exome

AF:

0.000143

AC:

200

AN:

1399352

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

107

AN XY:

690498

show subpopulations

African (AFR)

AF:

0.0000946

AC:

AN:

31728

American (AMR)

AF:

0.000614

AC:

AN:

35814

Ashkenazi Jewish (ASJ)

AF:

0.0000397

AC:

AN:

25162

East Asian (EAS)

AF:

0.00

AC:

AN:

36104

South Asian (SAS)

AF:

0.0000378

AC:

AN:

79326

European-Finnish (FIN)

AF:

0.000263

AC:

AN:

49450

Middle Eastern (MID)

AF:

0.000439

AC:

AN:

4552

European-Non Finnish (NFE)

AF:

0.000120

AC:

129

AN:

1079286

Other (OTH)

AF:

0.000466

AC:

AN:

57930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000386

AC:

AN:

150152

Hom.:

Cov.:

AF XY:

0.000436

AC XY:

AN XY:

73326

show subpopulations

African (AFR)

AF:

0.000124

AC:

AN:

40464

American (AMR)

AF:

0.00225

AC:

AN:

15126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000197

AC:

AN:

5072

South Asian (SAS)

AF:

0.00

AC:

AN:

4704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000193

AC:

AN:

67488

Other (OTH)

AF:

0.00194

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000171

Hom.:

Bravo

AF:

0.000616

ExAC

AF:

0.0000420

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

Uncertain

0.34

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

T;T;T;T;.

Eigen

Benign

0.021

Eigen_PC

Benign

-0.063

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.60

.;.;T;T;T

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.063

T;T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.4

M;M;M;.;.

PhyloP100

0.32

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.2

.;.;D;.;D

REVEL

Uncertain

0.33

Sift

Benign

0.046

.;.;D;.;T

Sift4G

Uncertain

0.032

.;.;D;D;D

Vest4

0.34, 0.37, 0.37

MutPred

0.69

Loss of methylation at R440 (P = 0.0071);Loss of methylation at R440 (P = 0.0071);Loss of methylation at R440 (P = 0.0071);.;.;

MVP

0.76

MPC

0.19

ClinPred

0.081

GERP RS

1.4

Varity_R

0.45

gMVP

0.48

Mutation Taster

=89/11

polymorphism

(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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22-42126749-C-T

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