22-42129809-T-C

Position:

• chr22-42129809-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000106.6(CYP2D6):​c.281A>G​(p.His94Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,574,218 control chromosomes in the GnomAD database, including 31,539 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1973 hom., cov: 30)
  • Exomes 𝑓: 0.16 (29566 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.587

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]

NDUFA6-DT (HGNC:45273): (NDUFA6 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001786828).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D6	NM_000106.6	c.281A>G	p.His94Arg	missense_variant	2/9	ENST00000645361.2
CYP2D6	NM_001025161.3	c.281A>G	p.His94Arg	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2	c.281A>G	p.His94Arg	missense_variant	2/9		NM_000106.6	P1
NDUFA6-DT	ENST00000439129.5	n.1718+4402T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18615 AN: 150216 Hom.: 1972 Cov.: 30

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.00292

Gnomad SAS AF: 0.0866

Gnomad FIN AF: 0.0934

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.0979 AC: 21941 AN: 224008 Hom.: 2390 AF XY: 0.0998 AC XY: 12262 AN XY: 122898

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.0614

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.000624

Gnomad SAS exome AF: 0.0597

Gnomad FIN exome AF: 0.0598

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.163 AC: 231429 AN: 1423892 Hom.: 29566 Cov.: 37 AF XY: 0.160 AC XY: 113682 AN XY: 708678

Gnomad4 AFR exome AF: 0.0314

Gnomad4 AMR exome AF: 0.0710

Gnomad4 ASJ exome AF: 0.176

Gnomad4 EAS exome AF: 0.000480

Gnomad4 SAS exome AF: 0.0845

Gnomad4 FIN exome AF: 0.0901

Gnomad4 NFE exome AF: 0.187

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.124 AC: 18609 AN: 150326 Hom.: 1973 Cov.: 30 AF XY: 0.116 AC XY: 8541 AN XY: 73400

Gnomad4 AFR AF: 0.0383

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.00273

Gnomad4 SAS AF: 0.0858

Gnomad4 FIN AF: 0.0934

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.123

Alfa AF: 0.101 Hom.: 252

Bravo AF: 0.123

ExAC AF: 0.112 AC: 13335

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

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
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.0050
DANN	Benign	0.16
DEOGEN2	Benign	0.00083	T;T;T;T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.036	N
MetaRNN	Benign	0.0018	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.84	L;L;L;.;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
Vest4		0.027, 0.069, 0.079
MPC		0.14
ClinPred		0.0099	T
GERP RS		-1.9
Varity_R		0.13
gMVP		0.55

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

Other links and lift over

dbSNP: rs28371704; hg19: chr22-42525811; COSMIC: COSV62242946; COSMIC: COSV62242946;