rs35742686

Variant names:

• chr22-42128241-CT-C
• rs35742686
• NM_000106.6:c.775delA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000106.6(CYP2D6):​c.775delA​(p.Arg259GlyfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,610,668 control chromosomes in the GnomAD database, including 957 homozygotes. Variant has been reported in ClinVar as Likely benign,other (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.012 (63 hom., cov: 31)
  • Exomes 𝑓: 0.015 (894 hom.)
• Consequence: CYP2D6 NM_000106.6 frameshift
• Clinical Significance: Likely benign; other criteria provided, multiple submitters, no conflicts B:1 O:2
• Conservation: PhyloP100: 0.218
• Publications: 221 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 -16 ACMG points.

• BP6: Variant 22-42128241-CT-C is Benign according to our data. Variant chr22-42128241-CT-C is described in ClinVar as Likely_benign|other. ClinVar VariationId is 16894.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 = 0.0123 (1854/151158) while in subpopulation NFE AF = 0.017 (1150/67728). AF 95% confidence interval is 0.0162. There are 63 homozygotes in GnomAd4. There are 929 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1854 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.775delA	p.Arg259GlyfsTer2	frameshift	Exon 5 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.622delA	p.Arg208GlyfsTer2	frameshift	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.775delA	p.Arg259GlyfsTer2	frameshift	Exon 5 of 9	ENSP00000496150.1	P10635-1
	CYP2D6	ENST00000359033.4	TSL:1	c.622delA	p.Arg208GlyfsTer2	frameshift	Exon 4 of 8	ENSP00000351927.4	P10635-2
	CYP2D6	ENST00000360124.10	TSL:1	n.622delA		non_coding_transcript_exon	Exon 4 of 8	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1854 AN: 151044 Hom.: 63 Cov.: 31

Gnomad AFR AF: 0.00321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00856

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.0361

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0126

GnomAD2 exomes AF: 0.0122 AC: 3049 AN: 249674 AF XY: 0.0120

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.00476

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0354

Gnomad NFE exome AF: 0.0172

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0155 AC: 22551 AN: 1459510 Hom.: 894 Cov.: 34 AF XY: 0.0149 AC XY: 10840 AN XY: 726018

African (AFR) AF: 0.00231 AC: 77 AN: 33324

American (AMR) AF: 0.00493 AC: 220 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00471 AC: 123 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00178 AC: 153 AN: 86074

European-Finnish (FIN) AF: 0.0338 AC: 1806 AN: 53388

Middle Eastern (MID) AF: 0.00365 AC: 21 AN: 5758

European-Non Finnish (NFE) AF: 0.0175 AC: 19464 AN: 1110336

Other (OTH) AF: 0.0114 AC: 687 AN: 60260

GnomAD4 genome AF: 0.0123 AC: 1854 AN: 151158 Hom.: 63 Cov.: 31 AF XY: 0.0126 AC XY: 929 AN XY: 73878

African (AFR) AF: 0.00320 AC: 131 AN: 40936

American (AMR) AF: 0.00855 AC: 130 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00167 AC: 8 AN: 4778

European-Finnish (FIN) AF: 0.0361 AC: 382 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0170 AC: 1150 AN: 67728

Other (OTH) AF: 0.0124 AC: 26 AN: 2090

Alfa AF: 0.0114 Hom.: 14

Bravo AF: 0.00999

Asia WGS AF: 0.00348 AC: 13 AN: 3466

ClinVar

ClinVar submissions

Significance: Likely benign; other

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.22
Mutation Taster		=153/47	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: rs35742686; hg19: chr22-42524243; COSMIC: COSV62243816;