22-42128128-C-T

Variant names:

• chr22-42128128-C-T
• rs28371722
• NM_000106.6:c.843+46G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -2.47
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 293 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.843+46G>A		intron_variant	Intron 5 of 8	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.690+46G>A		intron_variant	Intron 4 of 7		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.843+46G>A		intron_variant	Intron 5 of 8		NM_000106.6	ENSP00000496150.1

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 294 AN: 150722 Hom.: 13 Cov.: 32

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

GnomAD2 exomes AF: 0.00349 AC: 723 AN: 206944 AF XY: 0.00339

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 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.: 34 AF XY: 0.00189 AC XY: 1344 AN XY: 709576

African (AFR) AF: 0.00 AC: 0 AN: 32376

American (AMR) AF: 0.0000745 AC: 3 AN: 40246

Ashkenazi Jewish (ASJ) AF: 0.000507 AC: 13 AN: 25666

East Asian (EAS) AF: 0.0479 AC: 1847 AN: 38554

South Asian (SAS) AF: 0.000768 AC: 64 AN: 83308

European-Finnish (FIN) AF: 0.00813 AC: 423 AN: 52048

Middle Eastern (MID) AF: 0.00123 AC: 7 AN: 5672

European-Non Finnish (NFE) AF: 0.000226 AC: 247 AN: 1092806

Other (OTH) AF: 0.00156 AC: 92 AN: 59146

GnomAD4 genome AF: 0.00194 AC: 293 AN: 150834 Hom.: 13 Cov.: 32 AF XY: 0.00261 AC XY: 192 AN XY: 73698

African (AFR) AF: 0.000123 AC: 5 AN: 40784

American (AMR) AF: 0.00 AC: 0 AN: 15198

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

East Asian (EAS) AF: 0.0323 AC: 166 AN: 5134

South Asian (SAS) AF: 0.00147 AC: 7 AN: 4762

European-Finnish (FIN) AF: 0.00860 AC: 91 AN: 10580

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

European-Non Finnish (NFE) AF: 0.000325 AC: 22 AN: 67616

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000702 Hom.: 0

Asia WGS AF: 0.0170 AC: 59 AN: 3466

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	-0.91
CADD	Benign	0.56
DANN	Benign	0.51
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs28371722; hg19: chr22-42524130;