rs267608300

Positions:

• chr22-42128500-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000106.6(CYP2D6):​c.667-150G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,013,822 control chromosomes in the GnomAD database, including 131 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 0.0041 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (112 hom.)
• Consequence: CYP2D6 NM_000106.6 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -3.33

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BS2: High AC in GnomAd4 at 612 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.667-150G>A		intron_variant		ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.514-150G>A		intron_variant			NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.667-150G>A		intron_variant			NM_000106.6	ENSP00000496150	P1
NDUFA6-DT	ENST00000439129.5	n.1718+3093C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 611 AN: 150652 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.000986

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00303

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00520

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00650

Gnomad OTH AF: 0.00630

GnomAD4 exome AF: 0.00458 AC: 3956 AN: 863058 Hom.: 112 AF XY: 0.00449 AC XY: 1997 AN XY: 444678

Gnomad4 AFR exome AF: 0.000847

Gnomad4 AMR exome AF: 0.00256

Gnomad4 ASJ exome AF: 0.00200

Gnomad4 EAS exome AF: 0.0000282

Gnomad4 SAS exome AF: 0.000424

Gnomad4 FIN exome AF: 0.00695

Gnomad4 NFE exome AF: 0.00557

Gnomad4 OTH exome AF: 0.00394

GnomAD4 genome AF: 0.00406 AC: 612 AN: 150764 Hom.: 19 Cov.: 32 AF XY: 0.00382 AC XY: 281 AN XY: 73626

Gnomad4 AFR AF: 0.000983

Gnomad4 AMR AF: 0.00310

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00520

Gnomad4 NFE AF: 0.00650

Gnomad4 OTH AF: 0.00624

Alfa AF: 0.00672 Hom.: 5

Bravo AF: 0.00354

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
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.0050
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs267608300; hg19: chr22-42524502;