chr22-42129819-G-T

Position:

• chr22-42129819-G-T

Variant summary

Our verdict is Benign. Variant got -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). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.271C>A	p.Leu91Met	missense_variant	2/9	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.271C>A	p.Leu91Met	missense_variant	2/8		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.271C>A	p.Leu91Met	missense_variant	2/9		NM_000106.6	ENSP00000496150	P1
NDUFA6-DT	ENST00000439129.5	n.1718+4412G>T		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.0926 AC: 20371 AN: 219934 Hom.: 2280 AF XY: 0.0943 AC XY: 11395 AN XY: 120846

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 SAS exome AF: 0.0573

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

Gnomad4 AFR exome AF: 0.0293

Gnomad4 AMR exome AF: 0.0690

Gnomad4 ASJ exome AF: 0.169

Gnomad4 EAS exome AF: 0.000556

Gnomad4 SAS exome AF: 0.0824

Gnomad4 FIN exome AF: 0.0890

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome AF: 0.123 AC: 18458 AN: 150160 Hom.: 1939 Cov.: 30 AF XY: 0.116 AC XY: 8484 AN XY: 73324

Gnomad4 AFR AF: 0.0376

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.186

Gnomad4 EAS AF: 0.00273

Gnomad4 SAS AF: 0.0854

Gnomad4 FIN AF: 0.0929

Gnomad4 NFE AF: 0.192

Gnomad4 OTH AF: 0.122

Alfa AF: 0.156 Hom.: 446

Bravo AF: 0.122

ExAC AF: 0.109 AC: 12975

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Tramadol response Other:1

drug response, no assertion criteria provided

research

Bruce Budowle Laboratory, University of North Texas Health Science Center

Apr 28, 2018

- 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

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;T;T;T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.58	.;.;T;T;T
MetaRNN	Benign	0.0039	T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.4	M;M;M;.;M
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.7	.;.;N;.;N
REVEL	Uncertain	0.47
Sift	Benign	0.039	.;.;D;.;D
Sift4G	Uncertain	0.035	.;.;D;D;D
Vest4		0.15, 0.23, 0.25
MPC		0.52
ClinPred		0.093	T
GERP RS		2.4
Varity_R		0.12
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs28371703; hg19: chr22-42525821; COSMIC: COSV62242960; COSMIC: COSV62242960;