22-42130715-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000106.6(CYP2D6):c.77G>A(p.Arg26His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,602,016 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R26C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0058 ( 50 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 64 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.958

Publications

25 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=0.0043866336).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00585 (884/151146) while in subpopulation AFR AF = 0.0189 (773/40922). AF 95% confidence interval is 0.0178. There are 50 homozygotes in GnomAd4. There are 431 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 884 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.77G>A	p.Arg26His	missense_variant	Exon 1 of 9	ENST00000645361.2	NP_000097.3	P10635-1C1ID52Q5Y7H2
CYP2D6	NM_001025161.3 link	c.77G>A	p.Arg26His	missense_variant	Exon 1 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.77G>A	p.Arg26His	missense_variant	Exon 1 of 9		NM_000106.6	ENSP00000496150.1		P10635-1

Frequencies

GnomAD3 genomes

AF:

0.00587

AC:

886

AN:

151032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0190

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00257

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00691

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000428

Gnomad OTH

AF:

0.00434

GnomAD2 exomes

AF:

0.00223

AC:

524

AN:

235250

AF XY:

0.00203

show subpopulations

Gnomad AFR exome

AF:

0.0176

Gnomad AMR exome

AF:

0.00151

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000506

Gnomad FIN exome

AF:

0.000246

Gnomad NFE exome

AF:

0.000361

Gnomad OTH exome

AF:

0.00121

GnomAD4 exome

AF:

0.00106

AC:

1543

AN:

1450870

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

801

AN XY:

720880

show subpopulations

African (AFR)

AF:

0.0174

AC:

576

AN:

33170

American (AMR)

AF:

0.00202

AC:

AN:

43592

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25976

East Asian (EAS)

AF:

0.000356

AC:

AN:

39356

South Asian (SAS)

AF:

0.00493

AC:

417

AN:

84508

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52666

Middle Eastern (MID)

AF:

0.000530

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.000285

AC:

315

AN:

1106100

Other (OTH)

AF:

0.00214

AC:

128

AN:

59840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

174

262

349

436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00585

AC:

884

AN:

151146

Hom.:

Cov.:

AF XY:

0.00583

AC XY:

431

AN XY:

73866

show subpopulations

African (AFR)

AF:

0.0189

AC:

773

AN:

40922

American (AMR)

AF:

0.00257

AC:

AN:

15202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00692

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000428

AC:

AN:

67742

Other (OTH)

AF:

0.00430

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.123

Hom.:

3254

Bravo

AF:

0.00646

ESP6500AA

AF:

0.0168

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00249

AC:

302

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.022

T;T;T;T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.74

.;.;T;T;T

MetaRNN

Benign

0.0044

T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.0

L;L;L;.;L

PhyloP100

0.96

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.6

.;.;D;.;D

REVEL

Benign

0.26

Sift

Benign

0.090

.;.;T;.;T

Sift4G

Uncertain

0.059

.;.;T;T;T

Vest4

0.25, 0.33, 0.24

MVP

0.52

MPC

0.16

ClinPred

0.032

GERP RS

2.4

PromoterAI

0.023

Neutral

(source)

Varity_R

0.090

gMVP

0.46

Mutation Taster

=97/3

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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22-42130715-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over