22-42126390-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 publications found

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

Our verdict: Benign. The variant received -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

African (AFR) AF: 0.125 AC: 1721 AN: 13782

American (AMR) AF: 0.135 AC: 2453 AN: 18202

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 3377 AN: 13954

East Asian (EAS) AF: 0.441 AC: 13425 AN: 30434

South Asian (SAS) AF: 0.150 AC: 6184 AN: 41094

European-Finnish (FIN) AF: 0.119 AC: 4144 AN: 34838

Middle Eastern (MID) AF: 0.141 AC: 299 AN: 2114

European-Non Finnish (NFE) AF: 0.215 AC: 67910 AN: 315868

Other (OTH) AF: 0.204 AC: 5561 AN: 27320

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

African (AFR) AF: 0.123 AC: 4998 AN: 40756

American (AMR) AF: 0.152 AC: 2309 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 851 AN: 3466

East Asian (EAS) AF: 0.512 AC: 2562 AN: 5002

South Asian (SAS) AF: 0.165 AC: 786 AN: 4752

European-Finnish (FIN) AF: 0.114 AC: 1201 AN: 10578

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.222 AC: 14984 AN: 67480

Other (OTH) AF: 0.175 AC: 364 AN: 2080

Alfa AF: 0.153 Hom.: 795

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
PhyloP100		0.15

Splicing

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

Other links and lift over

dbSNP: rs28371738; hg19: chr22-42522392;