chr22-42129083-CA-C

Variant names:

• chr22-42129083-CA-C
• rs5030655
• NM_000106.6:c.454delT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000106.6(CYP2D6):​c.454delT​(p.Trp152GlyfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,609,822 control chromosomes in the GnomAD database, including 641 homozygotes. Variant has been reported in ClinVar as Likely benign,drug response,other (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0085 (39 hom., cov: 32)
  • Exomes 𝑓: 0.011 (602 hom.)
• Consequence: CYP2D6 NM_000106.6 frameshift
• Clinical Significance: Benign/Likely benign; drug response; other criteria provided, multiple submitters, no conflicts B:2 O:4
• Conservation: PhyloP100: -0.00600
• Publications: 186 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 -12 ACMG points.

• BP6: Variant 22-42129083-CA-C is Benign according to our data. Variant chr22-42129083-CA-C is described in ClinVar as Benign/Likely_benign|drug_response|other. ClinVar VariationId is 16891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1292 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.454delT	p.Trp152GlyfsTer2	frameshift	Exon 3 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.353-140delT		intron	N/A	NP_001020332.2	P10635-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	ENST00000645361.2	MANE Select	c.454delT	p.Trp152GlyfsTer2	frameshift	Exon 3 of 9	ENSP00000496150.1	P10635-1
	CYP2D6	ENST00000359033.4	TSL:1	c.353-140delT		intron	N/A	ENSP00000351927.4	P10635-2
	CYP2D6	ENST00000360124.10	TSL:1	n.353-140delT		intron	N/A	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes AF: 0.00852 AC: 1292 AN: 151570 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00538

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0246

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.00530

GnomAD2 exomes AF: 0.00792 AC: 1935 AN: 244380 AF XY: 0.00812

Gnomad AFR exome AF: 0.00212

Gnomad AMR exome AF: 0.00369

Gnomad ASJ exome AF: 0.00836

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0216

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.00591

GnomAD4 exome AF: 0.0110 AC: 16105 AN: 1458138 Hom.: 602 Cov.: 74 AF XY: 0.0107 AC XY: 7787 AN XY: 725324

African (AFR) AF: 0.00195 AC: 65 AN: 33318

American (AMR) AF: 0.00440 AC: 196 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 279 AN: 26082

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39554

South Asian (SAS) AF: 0.00208 AC: 179 AN: 85942

European-Finnish (FIN) AF: 0.0191 AC: 1011 AN: 52994

Middle Eastern (MID) AF: 0.00505 AC: 29 AN: 5742

European-Non Finnish (NFE) AF: 0.0125 AC: 13827 AN: 1109820

Other (OTH) AF: 0.00861 AC: 518 AN: 60160

GnomAD4 genome AF: 0.00852 AC: 1292 AN: 151684 Hom.: 39 Cov.: 32 AF XY: 0.00890 AC XY: 660 AN XY: 74152

African (AFR) AF: 0.00228 AC: 94 AN: 41230

American (AMR) AF: 0.00537 AC: 82 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00146 AC: 7 AN: 4808

European-Finnish (FIN) AF: 0.0246 AC: 261 AN: 10620

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0117 AC: 794 AN: 67850

Other (OTH) AF: 0.00525 AC: 11 AN: 2096

Alfa AF: 0.00177 Hom.: 4

Bravo AF: 0.00711

ClinVar

ClinVar submissions

Significance: Benign/Likely benign; drug response; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	-	Debrisoquine, poor metabolism of (1)
-	-	-	Deutetrabenazine response (1)
-	-	-	Tamoxifen response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.0060
Mutation Taster		=137/63	polymorphism (auto)

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: rs5030655; hg19: chr22-42525085; COSMIC: COSV100637415; COSMIC: COSV100637415;