rs28371706

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000106.6(CYP2D6):c.320C>T(p.Thr107Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,609,412 control chromosomes in the GnomAD database, including 2,087 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.052 ( 1019 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 1068 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

Clinical Significance

Likely benign; other criteria provided, multiple submitters, no conflicts B:2O:1

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 Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049679875).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.320C>T	p.Thr107Ile	missense_variant	2/9	ENST00000645361.2	NP_000097.3	P10635-1C1ID52Q5Y7H2
CYP2D6	NM_001025161.3 link	c.320C>T	p.Thr107Ile	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>T	p.Thr107Ile	missense_variant	2/9		NM_000106.6	ENSP00000496150.1		P10635-1

Frequencies

GnomAD3 genomes

AF:

0.0518

AC:

7830

AN:

151262

Hom.:

1010

Cov.:

show subpopulations

Gnomad AFR

AF:

0.181

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0142

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.0379

GnomAD3 exomes

AF:

0.0141

AC:

3431

AN:

244170

Hom.:

415

AF XY:

0.0109

AC XY:

1450

AN XY:

133408

show subpopulations

Gnomad AFR exome

AF:

0.185

Gnomad AMR exome

AF:

0.00717

Gnomad ASJ exome

AF:

0.0182

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00108

Gnomad FIN exome

AF:

0.000191

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.00799

GnomAD4 exome

AF:

0.00619

AC:

9031

AN:

1458040

Hom.:

1068

Cov.:

AF XY:

0.00544

AC XY:

3948

AN XY:

725406

show subpopulations

Gnomad4 AFR exome

AF:

0.196

Gnomad4 AMR exome

AF:

0.00920

Gnomad4 ASJ exome

AF:

0.0167

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00115

Gnomad4 FIN exome

AF:

0.000192

Gnomad4 NFE exome

AF:

0.000599

Gnomad4 OTH exome

AF:

0.0124

GnomAD4 genome

AF:

0.0519

AC:

7849

AN:

151372

Hom.:

1019

Cov.:

AF XY:

0.0496

AC XY:

3672

AN XY:

73974

show subpopulations

Gnomad4 AFR

AF:

0.181

Gnomad4 AMR

AF:

0.0142

Gnomad4 ASJ

AF:

0.0156

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00114

Gnomad4 OTH

AF:

0.0375

Alfa

AF:

0.0131

Hom.:

Bravo

AF:

0.0583

ESP6500AA

AF:

0.169

AC:

741

ESP6500EA

AF:

0.00175

AC:

ExAC

AF:

0.0178

AC:

2149

EpiCase

AF:

0.00186

EpiControl

AF:

0.00190

ClinVar

Significance: Likely benign; other

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 06, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.0060

DANN

Benign

0.81

DEOGEN2

Benign

0.00096

T;T;T;T;.

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0040

LIST_S2

Benign

0.055

.;.;T;T;T

MetaRNN

Benign

0.0050

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.070

N;N;N;.;N

PrimateAI

Benign

0.46

PROVEAN

Benign

0.41

.;.;N;.;N

REVEL

Benign

0.092

Sift

Benign

0.31

.;.;T;.;T

Sift4G

Benign

0.24

.;.;T;T;T

Vest4

0.069, 0.11, 0.085

MPC

0.12

ClinPred

0.0065

GERP RS

-1.7

Varity_R

0.16

gMVP

0.66

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over