rs1058172

Variant names:

• chr22-42127526-C-T
• rs1058172
• NM_000106.6:c.1094G>A
• CYP2D6 p.Arg365His

Your query was ambiguous. Multiple possible variants found:

• chr22-42127526-C-T
• chr22-42127526-C-G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BP4_Strong

The NM_000106.6(CYP2D6):​c.1094G>A​(p.Arg365His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.053 (5 hom., cov: 34)
  • Exomes 𝑓: 0.051 (58 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 7.72
• Publications: 50 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: Likely_benign. The variant received -3 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.018501878).

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.1094G>A	p.Arg365His	missense	Exon 7 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.941G>A	p.Arg314His	missense	Exon 6 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.1094G>A	p.Arg365His	missense	Exon 7 of 9	ENSP00000496150.1	P10635-1
	CYP2D6	ENST00000359033.4	TSL:1	c.941G>A	p.Arg314His	missense	Exon 6 of 8	ENSP00000351927.4	P10635-2
	CYP2D6	ENST00000360124.10	TSL:1	n.*169G>A		non_coding_transcript_exon	Exon 6 of 8	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes AF: 0.0535 AC: 7199 AN: 134436 Hom.: 5 Cov.: 34

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.0419

Gnomad ASJ AF: 0.0642

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.0338

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.0324

Gnomad NFE AF: 0.0915

Gnomad OTH AF: 0.0564

GnomAD2 exomes AF: 0.0917 AC: 21064 AN: 229594 AF XY: 0.0934

Gnomad AFR exome AF: 0.0244

Gnomad AMR exome AF: 0.0548

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.000819

Gnomad FIN exome AF: 0.0808

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.0931

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0511 AC: 62100 AN: 1214264 Hom.: 58 Cov.: 64 AF XY: 0.0509 AC XY: 30816 AN XY: 605814

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00602 AC: 194 AN: 32222

American (AMR) AF: 0.0125 AC: 516 AN: 41256

Ashkenazi Jewish (ASJ) AF: 0.0362 AC: 766 AN: 21182

East Asian (EAS) AF: 0.000278 AC: 11 AN: 39596

South Asian (SAS) AF: 0.0180 AC: 1407 AN: 78310

European-Finnish (FIN) AF: 0.0307 AC: 1462 AN: 47570

Middle Eastern (MID) AF: 0.0328 AC: 170 AN: 5178

European-Non Finnish (NFE) AF: 0.0619 AC: 55580 AN: 897914

Other (OTH) AF: 0.0391 AC: 1994 AN: 51036

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0535 AC: 7198 AN: 134560 Hom.: 5 Cov.: 34 AF XY: 0.0497 AC XY: 3285 AN XY: 66160

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0136 AC: 540 AN: 39686

American (AMR) AF: 0.0419 AC: 577 AN: 13782

Ashkenazi Jewish (ASJ) AF: 0.0642 AC: 177 AN: 2756

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5138

South Asian (SAS) AF: 0.0333 AC: 146 AN: 4382

European-Finnish (FIN) AF: 0.0395 AC: 379 AN: 9586

Middle Eastern (MID) AF: 0.0310 AC: 8 AN: 258

European-Non Finnish (NFE) AF: 0.0916 AC: 5157 AN: 56324

Other (OTH) AF: 0.0557 AC: 105 AN: 1886

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.123 Hom.: 91

ClinVar

ClinVar submissions

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
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Pathogenic	4.7	H
PhyloP100		7.7
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.69
gMVP		0.85
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1058172;

hg19: chr22-42523528;

COSMIC: COSV62242932;

COSMIC: COSV62242932;