22-42129770-G-T

Position:

chr22-42129770-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM5BP4_StrongBS2

The NM_000106.6(CYP2D6):c.320C>A(p.Thr107Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,608,900 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. T107I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00079 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 13 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.91

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 Likely_benign. Variant got -6 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-42129770-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.006817639).

BS2

High AC in GnomAd4 at 120 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.320C>A	p.Thr107Asn	missense_variant	2/9	ENST00000645361.2	NP_000097.3	P10635-1C1ID52Q5Y7H2
CYP2D6	NM_001025161.3 link	c.320C>A	p.Thr107Asn	missense_variant	2/8		NP_001020332.2	P10635-2Q5Y7H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2 link	c.320C>A	p.Thr107Asn	missense_variant	2/9		NM_000106.6	ENSP00000496150.1		P10635-1

Frequencies

GnomAD3 genomes

AF:

0.000793

AC:

120

AN:

151272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.0336

Gnomad AMR

AF:

0.00507

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000625

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000164

AC:

AN:

244170

Hom.:

AF XY:

0.000142

AC XY:

AN XY:

133408

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000915

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000547

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000178

AC:

260

AN:

1457518

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

120

AN XY:

725176

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00393

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000550

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000793

AC:

120

AN:

151382

Hom.:

Cov.:

AF XY:

0.000933

AC XY:

AN XY:

73972

show subpopulations

Gnomad4 AFR

AF:

0.0000244

Gnomad4 AMR

AF:

0.00506

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000626

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000475

ExAC

AF:

0.000827

AC:

100

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.0030

DANN

Benign

0.55

DEOGEN2

Benign

0.0011

T;T;T;T;.

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0021

LIST_S2

Benign

0.12

.;.;T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.0068

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.025

N;N;N;.;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.26

.;.;N;.;N

REVEL

Benign

0.14

Sift

Benign

0.31

.;.;T;.;T

Sift4G

Benign

0.22

.;.;T;T;T

Vest4

0.12, 0.13, 0.12

MutPred

0.52

Gain of relative solvent accessibility (P = 0.0905);Gain of relative solvent accessibility (P = 0.0905);Gain of relative solvent accessibility (P = 0.0905);.;Gain of relative solvent accessibility (P = 0.0905);

MVP

0.52

MPC

0.13

ClinPred

0.040

GERP RS

-1.7

Varity_R

0.19

gMVP

0.72

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