22-42126598-A-G

Variant names:

• chr22-42126598-A-G
• rs61731577
• NM_000106.6:c.1470T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_000106.6(CYP2D6):​c.1470T>C​(p.Tyr490Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,602,550 control chromosomes in the GnomAD database, including 17 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 0.00036 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (15 hom.)
• Consequence: CYP2D6 NM_000106.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.649
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP7: Synonymous conserved (PhyloP=0.649 with no splicing effect.
• BS2: High AC in GnomAd4 at 54 AD gene.

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.1470T>C	p.Tyr490Tyr	synonymous	Exon 9 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.1317T>C	p.Tyr439Tyr	synonymous	Exon 8 of 8	NP_001020332.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	ENST00000645361.2	MANE Select	c.1470T>C	p.Tyr490Tyr	synonymous	Exon 9 of 9	ENSP00000496150.1
	CYP2D6	ENST00000359033.4	TSL:1	c.1317T>C	p.Tyr439Tyr	synonymous	Exon 8 of 8	ENSP00000351927.4
	CYP2D6	ENST00000360124.10	TSL:1	n.*545T>C		non_coding_transcript_exon	Exon 8 of 8	ENSP00000353241.6

Frequencies

GnomAD3 genomes AF: 0.000346 AC: 52 AN: 150310 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000520

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00119

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000249 AC: 61 AN: 245202 AF XY: 0.000226

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.000626

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000554

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.000262

Gnomad OTH exome AF: 0.000505

GnomAD4 exome AF: 0.000236 AC: 342 AN: 1452126 Hom.: 15 Cov.: 32 AF XY: 0.000234 AC XY: 169 AN XY: 722140

African (AFR) AF: 0.000455 AC: 15 AN: 32938

American (AMR) AF: 0.000691 AC: 30 AN: 43384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25700

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39504

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85472

European-Finnish (FIN) AF: 0.0000564 AC: 3 AN: 53200

Middle Eastern (MID) AF: 0.000715 AC: 4 AN: 5596

European-Non Finnish (NFE) AF: 0.000233 AC: 258 AN: 1106412

Other (OTH) AF: 0.000367 AC: 22 AN: 59920

GnomAD4 genome AF: 0.000359 AC: 54 AN: 150424 Hom.: 2 Cov.: 33 AF XY: 0.000367 AC XY: 27 AN XY: 73508

African (AFR) AF: 0.000568 AC: 23 AN: 40500

American (AMR) AF: 0.00119 AC: 18 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5096

South Asian (SAS) AF: 0.00 AC: 0 AN: 4746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

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

European-Non Finnish (NFE) AF: 0.000192 AC: 13 AN: 67604

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000342 Hom.: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.64
DANN	Benign	0.52
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism

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: rs61731577; hg19: chr22-42522600;