chr22-42126462-G-A

Variant names:

• chr22-42126462-G-A
• rs28371737
• ENST00000439129.5:n.1718+1055G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000439129.5(NDUFA6-DT):​n.1718+1055G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00903 in 1,250,840 control chromosomes in the GnomAD database, including 9 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 0.0058 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0095 (8 hom.)
• Consequence: NDUFA6-DT ENST00000439129.5 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 0.234
• Publications: 1 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS2: High Homozygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.*112C>T		downstream_gene_variant		ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.*112C>T		downstream_gene_variant			NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.*112C>T		downstream_gene_variant			NM_000106.6	ENSP00000496150.1

Frequencies

GnomAD3 genomes AF: 0.00581 AC: 881 AN: 151506 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00993

Gnomad OTH AF: 0.00481

GnomAD4 exome AF: 0.00947 AC: 10410 AN: 1099216 Hom.: 8 Cov.: 16 AF XY: 0.00905 AC XY: 4895 AN XY: 540856

African (AFR) AF: 0.00198 AC: 49 AN: 24788

American (AMR) AF: 0.00233 AC: 48 AN: 20602

Ashkenazi Jewish (ASJ) AF: 0.000389 AC: 7 AN: 18010

East Asian (EAS) AF: 0.00 AC: 0 AN: 35376

South Asian (SAS) AF: 0.000559 AC: 33 AN: 58992

European-Finnish (FIN) AF: 0.00669 AC: 304 AN: 45434

Middle Eastern (MID) AF: 0.00122 AC: 4 AN: 3268

European-Non Finnish (NFE) AF: 0.0114 AC: 9600 AN: 845544

Other (OTH) AF: 0.00773 AC: 365 AN: 47202

GnomAD4 genome AF: 0.00581 AC: 881 AN: 151624 Hom.: 1 Cov.: 33 AF XY: 0.00546 AC XY: 405 AN XY: 74114

African (AFR) AF: 0.00236 AC: 97 AN: 41178

American (AMR) AF: 0.00190 AC: 29 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4794

European-Finnish (FIN) AF: 0.00650 AC: 69 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00993 AC: 674 AN: 67846

Other (OTH) AF: 0.00476 AC: 10 AN: 2100

Alfa AF: 0.00606 Hom.: 0

Bravo AF: 0.00550

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	-0.88
CADD	Benign	4.6
DANN	Benign	0.59
PhyloP100		0.23

Splicing

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

Other links and lift over

dbSNP: rs28371737; hg19: chr22-42522464;