22-42129819-G-T

Variant names:

• chr22-42129819-G-T
• rs28371703
• NM_000106.6:c.271C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000106.6(CYP2D6):​c.271C>A​(p.Leu91Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,535,588 control chromosomes in the GnomAD database, including 31,027 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.12 (1939 hom., cov: 30)
  • Exomes 𝑓: 0.15 (29088 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 0.482
• Publications: 46 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003934562).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

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.271C>A	p.Leu91Met	missense	Exon 2 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.271C>A	p.Leu91Met	missense	Exon 2 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.271C>A	p.Leu91Met	missense	Exon 2 of 9	ENSP00000496150.1	P10635-1
	CYP2D6	ENST00000359033.4	TSL:1	c.271C>A	p.Leu91Met	missense	Exon 2 of 8	ENSP00000351927.4	P10635-2
	CYP2D6	ENST00000360124.10	TSL:1	n.271C>A		non_coding_transcript_exon	Exon 2 of 8	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18464 AN: 150050 Hom.: 1938 Cov.: 30

Gnomad AFR AF: 0.0377

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.00291

Gnomad SAS AF: 0.0862

Gnomad FIN AF: 0.0929

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.0926 AC: 20371 AN: 219934 AF XY: 0.0943

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.0585

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.000684

Gnomad FIN exome AF: 0.0537

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.153 AC: 211871 AN: 1385428 Hom.: 29088 Cov.: 37 AF XY: 0.151 AC XY: 104369 AN XY: 690374

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

African (AFR) AF: 0.0293 AC: 968 AN: 32986

American (AMR) AF: 0.0690 AC: 3000 AN: 43484

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 4175 AN: 24760

East Asian (EAS) AF: 0.000556 AC: 22 AN: 39546

South Asian (SAS) AF: 0.0824 AC: 6944 AN: 84224

European-Finnish (FIN) AF: 0.0890 AC: 4375 AN: 49130

Middle Eastern (MID) AF: 0.0915 AC: 512 AN: 5598

European-Non Finnish (NFE) AF: 0.176 AC: 184202 AN: 1047690

Other (OTH) AF: 0.132 AC: 7673 AN: 58010

⚠️ 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 AF: 0.123 AC: 18458 AN: 150160 Hom.: 1939 Cov.: 30 AF XY: 0.116 AC XY: 8484 AN XY: 73324

African (AFR) AF: 0.0376 AC: 1537 AN: 40852

American (AMR) AF: 0.101 AC: 1520 AN: 15034

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 638 AN: 3434

East Asian (EAS) AF: 0.00273 AC: 14 AN: 5134

South Asian (SAS) AF: 0.0854 AC: 406 AN: 4754

European-Finnish (FIN) AF: 0.0929 AC: 980 AN: 10548

Middle Eastern (MID) AF: 0.0959 AC: 28 AN: 292

European-Non Finnish (NFE) AF: 0.192 AC: 12886 AN: 67176

Other (OTH) AF: 0.122 AC: 252 AN: 2074

Alfa AF: 0.152 Hom.: 446

Bravo AF: 0.122

ExAC AF: 0.109 AC: 12975

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	Benign	0.20
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0063	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		0.48
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.47
Sift	Benign	0.039	D
Sift4G	Uncertain	0.035	D
Vest4		0.15
MPC		0.52
ClinPred		0.093	T
GERP RS		2.4
Varity_R		0.12
gMVP		0.63
Mutation Taster		=94/6	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: rs28371703; hg19: chr22-42525821; COSMIC: COSV62242960; COSMIC: COSV62242960;