rs1081003

Variant names:

• chr22-42129754-G-A
• rs1081003
• NM_000106.6:c.336C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-42129754-G-A
• chr22-42129754-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000106.6(CYP2D6):​c.336C>T​(p.Phe112Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0457 in 1,609,512 control chromosomes in the GnomAD database, including 8,957 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.063 (1286 hom., cov: 32)
  • Exomes 𝑓: 0.044 (7671 hom.)
• Consequence: CYP2D6 NM_000106.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.98
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP7: Synonymous conserved (PhyloP=-1.98 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.336C>T	p.Phe112Phe	synonymous_variant	Exon 2 of 9	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.336C>T	p.Phe112Phe	synonymous_variant	Exon 2 of 8		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.336C>T	p.Phe112Phe	synonymous_variant	Exon 2 of 9		NM_000106.6	ENSP00000496150.1

Frequencies

GnomAD3 genomes AF: 0.0634 AC: 9592 AN: 151270 Hom.: 1288 Cov.: 32

Gnomad AFR AF: 0.0846

Gnomad AMI AF: 0.0455

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.537

Gnomad SAS AF: 0.0780

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0491

GnomAD2 exomes AF: 0.0788 AC: 19325 AN: 245240 AF XY: 0.0743

Gnomad AFR exome AF: 0.0852

Gnomad AMR exome AF: 0.0504

Gnomad ASJ exome AF: 0.0590

Gnomad EAS exome AF: 0.572

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.0251

Gnomad OTH exome AF: 0.0570

GnomAD4 exome AF: 0.0438 AC: 63897 AN: 1458130 Hom.: 7671 Cov.: 33 AF XY: 0.0441 AC XY: 32023 AN XY: 725446

African (AFR) AF: 0.0862 AC: 2875 AN: 33340

American (AMR) AF: 0.0514 AC: 2295 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 1505 AN: 26112

East Asian (EAS) AF: 0.479 AC: 18936 AN: 39562

South Asian (SAS) AF: 0.0646 AC: 5560 AN: 86108

European-Finnish (FIN) AF: 0.0188 AC: 979 AN: 52118

Middle Eastern (MID) AF: 0.0375 AC: 216 AN: 5764

European-Non Finnish (NFE) AF: 0.0249 AC: 27654 AN: 1110250

Other (OTH) AF: 0.0644 AC: 3877 AN: 60230

GnomAD4 genome AF: 0.0633 AC: 9585 AN: 151382 Hom.: 1286 Cov.: 32 AF XY: 0.0657 AC XY: 4862 AN XY: 73976

African (AFR) AF: 0.0844 AC: 3463 AN: 41048

American (AMR) AF: 0.0501 AC: 763 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 194 AN: 3470

East Asian (EAS) AF: 0.537 AC: 2749 AN: 5118

South Asian (SAS) AF: 0.0772 AC: 369 AN: 4780

European-Finnish (FIN) AF: 0.0163 AC: 173 AN: 10606

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0254 AC: 1725 AN: 67832

Other (OTH) AF: 0.0486 AC: 102 AN: 2100

Alfa AF: 0.0364 Hom.: 136

Bravo AF: 0.0697

Asia WGS AF: 0.231 AC: 798 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.82
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs1081003; hg19: chr22-42525756; COSMIC: COSV62243464; COSMIC: COSV62243464;