rs267608300

Variant names:

• chr22-42128500-C-T
• rs267608300
• NM_000106.6:c.667-150G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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 -8 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000106.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	NM_000106.6	MANE Select	c.667-150G>A		intron	N/A	NP_000097.3
	CYP2D6	NM_001025161.3		c.514-150G>A		intron	N/A	NP_001020332.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	ENST00000645361.2	MANE Select	c.667-150G>A		intron	N/A	ENSP00000496150.1
	CYP2D6	ENST00000359033.4	TSL:1	c.514-150G>A		intron	N/A	ENSP00000351927.4
	CYP2D6	ENST00000360124.10	TSL:1	n.514-150G>A		intron	N/A	ENSP00000353241.6

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

African (AFR) AF: 0.000847 AC: 18 AN: 21256

American (AMR) AF: 0.00256 AC: 89 AN: 34802

Ashkenazi Jewish (ASJ) AF: 0.00200 AC: 43 AN: 21482

East Asian (EAS) AF: 0.0000282 AC: 1 AN: 35400

South Asian (SAS) AF: 0.000424 AC: 29 AN: 68448

European-Finnish (FIN) AF: 0.00695 AC: 340 AN: 48954

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4080

European-Non Finnish (NFE) AF: 0.00557 AC: 3275 AN: 588066

Other (OTH) AF: 0.00394 AC: 160 AN: 40570

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

African (AFR) AF: 0.000983 AC: 40 AN: 40702

American (AMR) AF: 0.00310 AC: 47 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00520 AC: 55 AN: 10584

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

European-Non Finnish (NFE) AF: 0.00650 AC: 440 AN: 67660

Other (OTH) AF: 0.00624 AC: 13 AN: 2084

Alfa AF: 0.00672 Hom.: 5

Bravo AF: 0.00354

ClinVar

ClinVar submissions as Germline

Significance: drug response

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Tramadol response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.0050
DANN	Benign	0.61
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs267608300; hg19: chr22-42524502;