22-42129809-T-C

Variant names:

• chr22-42129809-T-C
• rs28371704
• NM_000106.6:c.281A>G

Variant summary

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

The NM_000106.6(CYP2D6):​c.281A>G​(p.His94Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,574,218 control chromosomes in the GnomAD database, including 31,539 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.12 (1973 hom., cov: 30)
  • Exomes 𝑓: 0.16 (29566 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.587
• Publications: 41 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=0.001786828).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.19 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	NM_000106.6	MANE Select	c.281A>G	p.His94Arg	missense	Exon 2 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.281A>G	p.His94Arg	missense	Exon 2 of 8	NP_001020332.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	ENST00000645361.2	MANE Select	c.281A>G	p.His94Arg	missense	Exon 2 of 9	ENSP00000496150.1
	CYP2D6	ENST00000359033.4	TSL:1	c.281A>G	p.His94Arg	missense	Exon 2 of 8	ENSP00000351927.4
	CYP2D6	ENST00000360124.10	TSL:1	n.281A>G		non_coding_transcript_exon	Exon 2 of 8	ENSP00000353241.6

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18615 AN: 150216 Hom.: 1972 Cov.: 30

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.00292

Gnomad SAS AF: 0.0866

Gnomad FIN AF: 0.0934

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.0979 AC: 21941 AN: 224008 AF XY: 0.0998

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.0614

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.000624

Gnomad FIN exome AF: 0.0598

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.163 AC: 231429 AN: 1423892 Hom.: 29566 Cov.: 37 AF XY: 0.160 AC XY: 113682 AN XY: 708678

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

African (AFR) AF: 0.0314 AC: 1041 AN: 33126

American (AMR) AF: 0.0710 AC: 3108 AN: 43780

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 4410 AN: 25026

East Asian (EAS) AF: 0.000480 AC: 19 AN: 39558

South Asian (SAS) AF: 0.0845 AC: 7161 AN: 84714

European-Finnish (FIN) AF: 0.0901 AC: 4476 AN: 49682

Middle Eastern (MID) AF: 0.0954 AC: 540 AN: 5662

European-Non Finnish (NFE) AF: 0.187 AC: 202433 AN: 1083234

Other (OTH) AF: 0.139 AC: 8241 AN: 59110

⚠️ 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: 0.124 AC: 18609 AN: 150326 Hom.: 1973 Cov.: 30 AF XY: 0.116 AC XY: 8541 AN XY: 73400

African (AFR) AF: 0.0383 AC: 1566 AN: 40862

American (AMR) AF: 0.103 AC: 1551 AN: 15084

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 649 AN: 3438

East Asian (EAS) AF: 0.00273 AC: 14 AN: 5128

South Asian (SAS) AF: 0.0858 AC: 409 AN: 4766

European-Finnish (FIN) AF: 0.0934 AC: 986 AN: 10558

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 12947 AN: 67246

Other (OTH) AF: 0.123 AC: 255 AN: 2078

Alfa AF: 0.0988 Hom.: 252

Bravo AF: 0.123

ExAC AF: 0.112 AC: 13335

ClinVar

ClinVar submissions as Germline

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	0.061
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.0050
DANN	Benign	0.16
DEOGEN2	Benign	0.00083	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.84	L
PhyloP100		-0.59
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.024
Sift	Benign	0.68	T
Sift4G	Benign	0.81	T
Vest4		0.027
MPC		0.14
ClinPred		0.0099	T
GERP RS		-1.9
Varity_R		0.13
gMVP		0.55
Mutation Taster		=100/0	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: rs28371704; hg19: chr22-42525811; COSMIC: COSV62242946; COSMIC: COSV62242946;