22-42126390-G-A

Variant names:

• chr22-42126390-G-A
• rs28371738
• ENST00000439129.5:n.1718+983G>A

Variant summary

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

The ENST00000439129.5(NDUFA6-DT):​n.1718+983G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 648,100 control chromosomes in the GnomAD database, including 17,575 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 0.19 (3782 hom., cov: 32)
  • Exomes 𝑓: 0.21 (13793 hom.)
• Consequence: NDUFA6-DT ENST00000439129.5 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 0.151

Genes affected

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

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.*184C>T		downstream_gene_variant		ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.*184C>T		downstream_gene_variant			NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.*184C>T		downstream_gene_variant			NM_000106.6	ENSP00000496150.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28373 AN: 150378 Hom.: 3786 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.512

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.178

GnomAD4 exome AF: 0.211 AC: 105074 AN: 497606 Hom.: 13793 AF XY: 0.210 AC XY: 53900 AN XY: 256990

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.242

Gnomad4 EAS exome AF: 0.441

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.119

Gnomad4 NFE exome AF: 0.215

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.188 AC: 28356 AN: 150494 Hom.: 3782 Cov.: 32 AF XY: 0.183 AC XY: 13467 AN XY: 73488

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.246

Gnomad4 EAS AF: 0.512

Gnomad4 SAS AF: 0.165

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.222

Gnomad4 OTH AF: 0.175

Alfa AF: 0.107 Hom.: 194

Bravo AF: 0.191

Asia WGS AF: 0.285 AC: 986 AN: 3456

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Tramadol response Other:1

Apr 28, 2018

Bruce Budowle Laboratory, University of North Texas Health Science Center

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

- 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	-0.96
CADD	Benign	2.6
DANN	Benign	0.35

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28371738; hg19: chr22-42522392;