Variant rs16947 details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000106.6(CYP2D6):c.886C>T(p.Arg296Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 1,610,098 control chromosomes in the GnomAD database, including 108,422 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.39 ( 13067 hom., cov: 32)

Exomes 𝑓: 0.34 ( 95355 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.921

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=0.008255243).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6 linkuse as main transcript	c.886C>T	p.Arg296Cys	missense_variant	6/9	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3 linkuse as main transcript	c.733C>T	p.Arg245Cys	missense_variant	5/8		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2 linkuse as main transcript	c.886C>T	p.Arg296Cys	missense_variant	6/9		NM_000106.6	ENSP00000496150	P1	P10635-1
NDUFA6-DT	ENST00000439129.5 linkuse as main transcript	n.1718+2534G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.385

AC:

58085

AN:

150702

Hom.:

13023

Cov.:

show subpopulations

Gnomad AFR

AF:

0.517

Gnomad AMI

AF:

0.231

Gnomad AMR

AF:

0.343

Gnomad ASJ

AF:

0.394

Gnomad EAS

AF:

0.149

Gnomad SAS

AF:

0.381

Gnomad FIN

AF:

0.389

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.335

Gnomad OTH

AF:

0.382

GnomAD4 exome

AF:

0.336

AC:

490905

AN:

1459282

Hom.:

95355

Cov.:

AF XY:

0.339

AC XY:

245894

AN XY:

725958

show subpopulations

Gnomad4 AFR exome

AF:

0.527

Gnomad4 AMR exome

AF:

0.285

Gnomad4 ASJ exome

AF:

0.406

Gnomad4 EAS exome

AF:

0.144

Gnomad4 SAS exome

AF:

0.384

Gnomad4 FIN exome

AF:

0.387

Gnomad4 NFE exome

AF:

0.330

Gnomad4 OTH exome

AF:

0.354

GnomAD4 genome

AF:

0.386

AC:

58174

AN:

150816

Hom.:

13067

Cov.:

AF XY:

0.386

AC XY:

28466

AN XY:

73670

show subpopulations

Gnomad4 AFR

AF:

0.518

Gnomad4 AMR

AF:

0.344

Gnomad4 ASJ

AF:

0.394

Gnomad4 EAS

AF:

0.148

Gnomad4 SAS

AF:

0.382

Gnomad4 FIN

AF:

0.389

Gnomad4 NFE

AF:

0.335

Gnomad4 OTH

AF:

0.378

Alfa

AF:

0.322

Hom.:

2728

Bravo

AF:

0.386

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 27, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_noAF

Benign

-0.92

CADD

Benign

DEOGEN2

Benign

0.017

T;T;T;T;.

LIST_S2

Benign

0.26

.;.;T;T;T

MetaRNN

Benign

0.0083

T;T;T;T;T

Sift4G

Benign

0.18

.;.;T;T;T

Vest4

0.17, 0.18, 0.19

gMVP

0.61

Splicing

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