rs5030656

Variant names:

• chr22-42128173-CCTT-C
• rs5030656
• NM_000106.6:c.841_843delAAG

Your query was ambiguous. Multiple possible variants found:

• chr22-42128173-CCTT-C
• chr22-42128173-CCTT-CCTTCTT

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM4_Supporting PP3_Moderate BP6_Very_Strong BS1 BS2

The NM_000106.6(CYP2D6):​c.841_843delAAG​(p.Lys281del) variant causes a conservative inframe deletion, splice region change. The variant allele was found at a frequency of 0.0249 in 1,604,474 control chromosomes in the GnomAD database, including 1,878 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign,other (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (132 hom., cov: 31)
  • Exomes 𝑓: 0.026 (1746 hom.)
• Consequence: CYP2D6 NM_000106.6 conservative_inframe_deletion, splice_region
• Clinical Significance: Likely benign; other criteria provided, multiple submitters, no conflicts B:1 O:2
• Conservation: PhyloP100: 4.46
• Publications: 153 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 -13 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000106.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 22-42128173-CCTT-C is Benign according to our data. Variant chr22-42128173-CCTT-C is described in ClinVar as Likely_benign|other. ClinVar VariationId is 617719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0177 (2664/150750) while in subpopulation NFE AF = 0.0285 (1924/67614). AF 95% confidence interval is 0.0274. There are 132 homozygotes in GnomAd4. There are 1242 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2664 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.841_843delAAG	p.Lys281del	conservative_inframe_deletion splice_region	Exon 5 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.688_690delAAG	p.Lys230del	conservative_inframe_deletion splice_region	Exon 4 of 8	NP_001020332.2	P10635-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	ENST00000645361.2	MANE Select	c.841_843delAAG	p.Lys281del	conservative_inframe_deletion splice_region	Exon 5 of 9	ENSP00000496150.1	P10635-1
	CYP2D6	ENST00000359033.4	TSL:1	c.688_690delAAG	p.Lys230del	conservative_inframe_deletion splice_region	Exon 4 of 8	ENSP00000351927.4	P10635-2
	CYP2D6	ENST00000360124.10	TSL:1	n.688_690delAAG		splice_region non_coding_transcript_exon	Exon 4 of 8	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2666 AN: 150638 Hom.: 132 Cov.: 31

Gnomad AFR AF: 0.00549

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000631

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0285

Gnomad OTH AF: 0.0184

GnomAD2 exomes AF: 0.0154 AC: 3675 AN: 238732 AF XY: 0.0152

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.00315

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0177

GnomAD4 exome AF: 0.0256 AC: 37232 AN: 1453724 Hom.: 1746 AF XY: 0.0249 AC XY: 17975 AN XY: 722536

African (AFR) AF: 0.00377 AC: 125 AN: 33164

American (AMR) AF: 0.0139 AC: 610 AN: 43796

Ashkenazi Jewish (ASJ) AF: 0.00327 AC: 85 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39438

South Asian (SAS) AF: 0.00266 AC: 226 AN: 85036

European-Finnish (FIN) AF: 0.0135 AC: 719 AN: 53090

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5734

European-Non Finnish (NFE) AF: 0.0308 AC: 34095 AN: 1107434

Other (OTH) AF: 0.0227 AC: 1362 AN: 60020

GnomAD4 genome AF: 0.0177 AC: 2664 AN: 150750 Hom.: 132 Cov.: 31 AF XY: 0.0169 AC XY: 1242 AN XY: 73646

African (AFR) AF: 0.00548 AC: 223 AN: 40730

American (AMR) AF: 0.0204 AC: 310 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.000631 AC: 3 AN: 4754

European-Finnish (FIN) AF: 0.0146 AC: 155 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0285 AC: 1924 AN: 67614

Other (OTH) AF: 0.0183 AC: 38 AN: 2082

Alfa AF: 0.0188 Hom.: 23

Bravo AF: 0.0175

Asia WGS AF: 0.00116 AC: 4 AN: 3464

ClinVar

ClinVar submissions

Significance: Likely benign; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (2)
-	-	-	Tramadol response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5
Mutation Taster		=52/48	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		1.0		Position offset: 4
DS_DL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs5030656; hg19: chr22-42524175; COSMIC: COSV62242923; COSMIC: COSV62242923;