chr22-42128173-CCTT-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PM4_Supporting 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

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 -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000106.6. Strenght limited to Supporting due to length of the change: 1aa.
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2664 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.841_843delAAG	p.Lys281del	conservative_inframe_deletion, splice_region_variant	Exon 5 of 9	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.688_690delAAG	p.Lys230del	conservative_inframe_deletion, splice_region_variant	Exon 4 of 8		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.841_843delAAG	p.Lys281del	conservative_inframe_deletion, splice_region_variant	Exon 5 of 9		NM_000106.6	ENSP00000496150.1

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

GnomAD3 exomes AF: 0.0154 AC: 3675 AN: 238732 Hom.: 137 AF XY: 0.0152 AC XY: 1963 AN XY: 129004

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 SAS exome AF: 0.00212

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

Gnomad4 AFR exome AF: 0.00377

Gnomad4 AMR exome AF: 0.0139

Gnomad4 ASJ exome AF: 0.00327

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00266

Gnomad4 FIN exome AF: 0.0135

Gnomad4 NFE exome AF: 0.0308

Gnomad4 OTH exome AF: 0.0227

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

Gnomad4 AFR AF: 0.00548

Gnomad4 AMR AF: 0.0204

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000631

Gnomad4 FIN AF: 0.0146

Gnomad4 NFE AF: 0.0285

Gnomad4 OTH AF: 0.0183

Alfa AF: 0.0188 Hom.: 23

Bravo AF: 0.0175

Asia WGS AF: 0.00116 AC: 4 AN: 3464

ClinVar

Significance: Likely benign; other

Submissions summary: Benign:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

Apr 12, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aug 06, 2018

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs5030656; hg19: chr22-42524175;