22-42129075-C-T

Position:

chr22-42129075-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP5BP4BS1_SupportingBS2

The NM_000106.6(CYP2D6):c.463G>A(p.Glu155Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,609,096 control chromosomes in the GnomAD database, including 237 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.013 ( 130 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 107 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.295

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 -5 ACMG points.

PP5

Variant 22-42129075-C-T is Pathogenic according to our data. Variant chr22-42129075-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.006427139). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0126 (1908/151520) while in subpopulation AFR AF= 0.0438 (1802/41172). AF 95% confidence interval is 0.0421. There are 130 homozygotes in gnomad4. There are 941 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 1908 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.463G>A	p.Glu155Lys	missense_variant	3/9	ENST00000645361.2	NP_000097.3	P10635-1C1ID52Q5Y7H2
CYP2D6	NM_001025161.3 link	c.353-131G>A		intron_variant			NP_001020332.2	P10635-2Q5Y7H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2 link	c.463G>A	p.Glu155Lys	missense_variant	3/9		NM_000106.6	ENSP00000496150.1		P10635-1

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1897

AN:

151406

Hom.:

129

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0436

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00571

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00578

GnomAD3 exomes

AF:

0.00319

AC:

775

AN:

242812

Hom.:

AF XY:

0.00250

AC XY:

331

AN XY:

132500

show subpopulations

Gnomad AFR exome

AF:

0.0454

Gnomad AMR exome

AF:

0.00297

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000133

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000821

Gnomad OTH exome

AF:

0.00153

GnomAD4 exome

AF:

0.00121

AC:

1763

AN:

1457576

Hom.:

107

Cov.:

AF XY:

0.00109

AC XY:

793

AN XY:

725002

show subpopulations

Gnomad4 AFR exome

AF:

0.0420

Gnomad4 AMR exome

AF:

0.00331

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000140

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.00271

GnomAD4 genome

AF:

0.0126

AC:

1908

AN:

151520

Hom.:

130

Cov.:

AF XY:

0.0127

AC XY:

941

AN XY:

74052

show subpopulations

Gnomad4 AFR

AF:

0.0438

Gnomad4 AMR

AF:

0.00570

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00572

Alfa

AF:

0.000943

Hom.:

Bravo

AF:

0.0144

ESP6500AA

AF:

0.0361

AC:

151

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.00354

AC:

427

Asia WGS

AF:

0.00203

AC:

AN:

3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.016

T;T;T;T

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.76

.;.;T;T

MetaRNN

Benign

0.0064

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;L;L;.

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.8

.;.;D;.

REVEL

Benign

0.12

Sift

Benign

0.13

.;.;T;.

Sift4G

Benign

0.097

.;.;T;T

Vest4

0.37, 0.39

MVP

0.44

MPC

0.16

ClinPred

0.0064

GERP RS

-2.7

Varity_R

0.21

gMVP

0.69

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