22-42129130-C-G

Variant names:

• chr22-42129130-C-G
• rs1058164
• NM_000106.6:c.408G>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.408G>C​(p.Val136Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 150,534 control chromosomes in the GnomAD database, including 26,082 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 0.57 (26082 hom., cov: 34)
  • Exomes 𝑓: 0.52 (196805 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP2D6 NM_000106.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.58
• Publications: 100 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=-0.91).
• BP7: Synonymous conserved (PhyloP=-2.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.67 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.408G>C	p.Val136Val	synonymous	Exon 3 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.353-186G>C		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.408G>C	p.Val136Val	synonymous	Exon 3 of 9	ENSP00000496150.1
	CYP2D6	ENST00000359033.4	TSL:1	c.353-186G>C		intron	N/A	ENSP00000351927.4
	CYP2D6	ENST00000360124.10	TSL:1	n.353-186G>C		intron	N/A	ENSP00000353241.6

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86080 AN: 150426 Hom.: 26052 Cov.: 34

Gnomad AFR AF: 0.638

Gnomad AMI AF: 0.517

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.558

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.525 AC: 752046 AN: 1433080 Hom.: 196805 Cov.: 69 AF XY: 0.527 AC XY: 376050 AN XY: 713826

African (AFR) AF: 0.624 AC: 20317 AN: 32576

American (AMR) AF: 0.396 AC: 17505 AN: 44260

Ashkenazi Jewish (ASJ) AF: 0.635 AC: 16382 AN: 25780

East Asian (EAS) AF: 0.622 AC: 24574 AN: 39518

South Asian (SAS) AF: 0.532 AC: 45449 AN: 85374

European-Finnish (FIN) AF: 0.491 AC: 25411 AN: 51776

Middle Eastern (MID) AF: 0.557 AC: 3184 AN: 5712

European-Non Finnish (NFE) AF: 0.521 AC: 566711 AN: 1088616

Other (OTH) AF: 0.547 AC: 32513 AN: 59468

GnomAD4 genome AF: 0.572 AC: 86147 AN: 150534 Hom.: 26082 Cov.: 34 AF XY: 0.568 AC XY: 41805 AN XY: 73540

African (AFR) AF: 0.638 AC: 26085 AN: 40854

American (AMR) AF: 0.488 AC: 7415 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 2205 AN: 3454

East Asian (EAS) AF: 0.689 AC: 3522 AN: 5114

South Asian (SAS) AF: 0.554 AC: 2633 AN: 4756

European-Finnish (FIN) AF: 0.500 AC: 5264 AN: 10526

Middle Eastern (MID) AF: 0.632 AC: 182 AN: 288

European-Non Finnish (NFE) AF: 0.553 AC: 37226 AN: 67376

Other (OTH) AF: 0.553 AC: 1156 AN: 2090

Alfa AF: 0.576 Hom.: 4799

Bravo AF: 0.575

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0
PhyloP100		-2.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1058164; hg19: chr22-42525132;