chr22-42129132-C-T

Variant names:

• chr22-42129132-C-T
• rs61736512
• NM_000106.6:c.406G>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.406G>A​(p.Val136Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,609,922 control chromosomes in the GnomAD database, including 523 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.026 (357 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (166 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.89
• Publications: 60 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=0.002351731).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0884 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.406G>A	p.Val136Met	missense	Exon 3 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.353-188G>A		intron	N/A	NP_001020332.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	ENST00000645361.2	MANE Select	c.406G>A	p.Val136Met	missense	Exon 3 of 9	ENSP00000496150.1
	CYP2D6	ENST00000359033.4	TSL:1	c.353-188G>A		intron	N/A	ENSP00000351927.4
	CYP2D6	ENST00000360124.10	TSL:1	n.353-188G>A		intron	N/A	ENSP00000353241.6

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3959 AN: 151462 Hom.: 357 Cov.: 33

Gnomad AFR AF: 0.0909

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00951

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000575

Gnomad OTH AF: 0.0179

GnomAD2 exomes AF: 0.00668 AC: 1640 AN: 245456 AF XY: 0.00502

Gnomad AFR exome AF: 0.0951

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.00210

Gnomad EAS exome AF: 0.000504

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000233

Gnomad OTH exome AF: 0.00284

GnomAD4 exome AF: 0.00265 AC: 3868 AN: 1458348 Hom.: 166 Cov.: 37 AF XY: 0.00227 AC XY: 1646 AN XY: 725544

African (AFR) AF: 0.0916 AC: 3051 AN: 33314

American (AMR) AF: 0.00464 AC: 207 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26102

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39592

South Asian (SAS) AF: 0.000314 AC: 27 AN: 86102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52430

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5764

European-Non Finnish (NFE) AF: 0.000154 AC: 171 AN: 1110186

Other (OTH) AF: 0.00560 AC: 337 AN: 60226

GnomAD4 genome AF: 0.0262 AC: 3967 AN: 151574 Hom.: 357 Cov.: 33 AF XY: 0.0244 AC XY: 1808 AN XY: 74090

African (AFR) AF: 0.0908 AC: 3736 AN: 41138

American (AMR) AF: 0.00950 AC: 145 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5154

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000575 AC: 39 AN: 67846

Other (OTH) AF: 0.0177 AC: 37 AN: 2094

Alfa AF: 0.00490 Hom.: 31

Bravo AF: 0.0307

ESP6500AA AF: 0.0877 AC: 356

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.00830 AC: 1003

Asia WGS AF: 0.00579 AC: 20 AN: 3468

EpiCase AF: 0.000273

EpiControl AF: 0.000238

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.35
DANN	Benign	0.93
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0024	T
PhyloP100		-1.9
PROVEAN	Benign	-1.4	N
Sift	Benign	0.042	D
Sift4G	Uncertain	0.022	D
Vest4		0.16
MVP		0.26
ClinPred		0.0070	T
GERP RS		-8.2
Varity_R		0.11
gMVP		0.44
Mutation Taster		=97/3	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: rs61736512; hg19: chr22-42525134; COSMIC: COSV62243446;