22-42129906-G-C

Variant names:

• chr22-42129906-G-C
• rs267608311
• NM_000106.6:c.184C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000106.6(CYP2D6):​c.184C>G​(p.Arg62Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,413,586 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0370
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.184C>G	p.Arg62Gly	missense	Exon 2 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.184C>G	p.Arg62Gly	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.184C>G	p.Arg62Gly	missense	Exon 2 of 9	ENSP00000496150.1	P10635-1
	CYP2D6	ENST00000359033.4	TSL:1	c.184C>G	p.Arg62Gly	missense	Exon 2 of 8	ENSP00000351927.4	P10635-2
	CYP2D6	ENST00000360124.10	TSL:1	n.184C>G		non_coding_transcript_exon	Exon 2 of 8	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.00 AC: 0 AN: 174020 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1413586 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 701272

African (AFR) AF: 0.00 AC: 0 AN: 32570

American (AMR) AF: 0.00 AC: 0 AN: 39356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25460

East Asian (EAS) AF: 0.00 AC: 0 AN: 38630

South Asian (SAS) AF: 0.00 AC: 0 AN: 82850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4866

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1087444

Other (OTH) AF: 0.00 AC: 0 AN: 58602

GnomAD4 genome Cov.: 28

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000891 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.037
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.43
Sift	Benign	0.19	T
Sift4G	Benign	0.38	T
Vest4		0.33
MutPred		0.71		Loss of MoRF binding (P = 0.2116)
MVP		0.69
MPC		0.25
ClinPred		0.76	D
GERP RS		1.3
Varity_R		0.35
gMVP		0.77
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267608311; hg19: chr22-42525908;