22-42126598-A-G

Position:

• chr22-42126598-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 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. Variant has been reported in Lovd as Benign (no stars).

• 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

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]

CYP2D6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 22-42126598-A-G is Benign according to our data. Variant chr22-42126598-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.649 with no splicing effect.
• BS2: High AC in GnomAd4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.1470T>C	p.Tyr490Tyr	synonymous_variant	9/9	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.1317T>C	p.Tyr439Tyr	synonymous_variant	8/8		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.1470T>C	p.Tyr490Tyr	synonymous_variant	9/9		NM_000106.6	ENSP00000496150.1

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

GnomAD3 exomes AF: 0.000249 AC: 61 AN: 245202 Hom.: 1 AF XY: 0.000226 AC XY: 30 AN XY: 132842

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 SAS exome AF: 0.0000664

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

Gnomad4 AFR exome AF: 0.000455

Gnomad4 AMR exome AF: 0.000691

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.0000564

Gnomad4 NFE exome AF: 0.000233

Gnomad4 OTH exome AF: 0.000367

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

Gnomad4 AFR AF: 0.000568

Gnomad4 AMR AF: 0.00119

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000192

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000325 Hom.: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.64
DANN	Benign	0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs61731577; hg19: chr22-42522600;