22-42128128-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000106.6(CYP2D6):c.843+46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,580,656 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 163 hom. )

Consequence

CYP2D6
NM_000106.6 intron

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: -2.47

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00194 (293/150834) while in subpopulation EAS AF= 0.0323 (166/5134). AF 95% confidence interval is 0.0283. There are 13 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd at 294 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D6	NM_000106.6 linkuse as main transcript	c.843+46G>A		intron_variant		ENST00000645361.2
CYP2D6	NM_001025161.3 linkuse as main transcript	c.690+46G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2 linkuse as main transcript	c.843+46G>A		intron_variant			NM_000106.6	P1	P10635-1
NDUFA6-DT	ENST00000439129.5 linkuse as main transcript	n.1718+2721C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

294

AN:

150722

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0323

Gnomad SAS

AF:

0.00168

Gnomad FIN

AF:

0.00860

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000325

Gnomad OTH

AF:

0.000484

GnomAD3 exomes

AF:

0.00349

AC:

723

AN:

206944

Hom.:

AF XY:

0.00339

AC XY:

378

AN XY:

111518

show subpopulations

Gnomad AFR exome

AF:

0.0000825

Gnomad AMR exome

AF:

0.000102

Gnomad ASJ exome

AF:

0.000538

Gnomad EAS exome

AF:

0.0301

Gnomad SAS exome

AF:

0.000740

Gnomad FIN exome

AF:

0.00840

Gnomad NFE exome

AF:

0.000328

Gnomad OTH exome

AF:

0.00303

GnomAD4 exome

AF:

0.00189

AC:

2696

AN:

1429822

Hom.:

163

Cov.:

AF XY:

0.00189

AC XY:

1344

AN XY:

709576

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000745

Gnomad4 ASJ exome

AF:

0.000507

Gnomad4 EAS exome

AF:

0.0479

Gnomad4 SAS exome

AF:

0.000768

Gnomad4 FIN exome

AF:

0.00813

Gnomad4 NFE exome

AF:

0.000226

Gnomad4 OTH exome

AF:

0.00156

GnomAD4 genome

AF:

0.00194

AC:

293

AN:

150834

Hom.:

Cov.:

AF XY:

0.00261

AC XY:

192

AN XY:

73698

show subpopulations

Gnomad4 AFR

AF:

0.000123

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0323

Gnomad4 SAS

AF:

0.00147

Gnomad4 FIN

AF:

0.00860

Gnomad4 NFE

AF:

0.000325

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.00123

Hom.:

Asia WGS

AF:

0.0170

AC:

AN:

3466

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Tramadol response

Other:1

drug response, no assertion criteria provided

research

Bruce Budowle Laboratory, University of North Texas Health Science Center

Apr 28, 2018

- T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

Cadd

Benign

0.56

Dann

Benign

0.51

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