22-42130715-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043866336).

BP6

Variant 22-42130715-C-T is Benign according to our data. Variant chr22-42130715-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

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	UniProt
CYP2D6	ENST00000645361.2 link	c.77G>A	p.Arg26His	missense_variant	Exon 1 of 9		NM_000106.6	ENSP00000496150.1	P10635-1
CYP2D6	ENST00000359033.4 link	c.77G>A	p.Arg26His	missense_variant	Exon 1 of 8	1		ENSP00000351927.4	P10635-2
CYP2D6	ENST00000488442.1 link	n.99G>A		non_coding_transcript_exon_variant	Exon 1 of 8	5
NDUFA6-DT	ENST00000439129.5 link	n.1718+5308C>T		intron_variant	Intron 5 of 6	5

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

GnomAD3 exomes

AF:

0.00223

AC:

524

AN:

235250

Hom.:

AF XY:

0.00203

AC XY:

259

AN XY:

127486

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 SAS exome

AF:

0.00553

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

Gnomad4 AFR exome

AF:

0.0174

Gnomad4 AMR exome

AF:

0.00202

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.000356

Gnomad4 SAS exome

AF:

0.00493

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.000285

Gnomad4 OTH exome

AF:

0.00214

GnomAD4 genome

AF:

0.00585

AC:

884

AN:

151146

Hom.:

Cov.:

AF XY:

0.00583

AC XY:

431

AN XY:

73866

show subpopulations

Gnomad4 AFR

AF:

0.0189

Gnomad4 AMR

AF:

0.00257

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00692

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000428

Gnomad4 OTH

AF:

0.00430

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

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

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

Varity_R

0.090

gMVP

0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over