22-42130967-C-T

Variant names:

• chr22-42130967-C-T
• rs1080993
• ENST00000852651.1:c.-176G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000852651.1(CYP2D6):​c.-176G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00862 in 713,066 control chromosomes in the GnomAD database, including 515 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 0.027 (364 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (151 hom.)
• Consequence: CYP2D6 ENST00000852651.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.387
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0921 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000852651.1. 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.-176G>A		upstream_gene	N/A	NP_000097.3
	CYP2D6	NM_001025161.3		c.-176G>A		upstream_gene	N/A	NP_001020332.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	ENST00000852651.1		c.-176G>A		5_prime_UTR	Exon 1 of 9	ENSP00000522710.1
	NDUFA6-DT	ENST00000439129.5	TSL:5	n.1719-5232C>T		intron	N/A
	CYP2D6	ENST00000645361.2	MANE Select	c.-176G>A		upstream_gene	N/A	ENSP00000496150.1

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4091 AN: 151152 Hom.: 362 Cov.: 31

Gnomad AFR AF: 0.0946

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00953

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000590

Gnomad OTH AF: 0.0198

GnomAD4 exome AF: 0.00363 AC: 2041 AN: 561802 Hom.: 151 AF XY: 0.00299 AC XY: 878 AN XY: 293968

African (AFR) AF: 0.0993 AC: 1523 AN: 15344

American (AMR) AF: 0.00526 AC: 154 AN: 29296

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 32 AN: 16430

East Asian (EAS) AF: 0.00 AC: 0 AN: 32118

South Asian (SAS) AF: 0.000361 AC: 19 AN: 52608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40448

Middle Eastern (MID) AF: 0.00442 AC: 10 AN: 2264

European-Non Finnish (NFE) AF: 0.000271 AC: 93 AN: 343282

Other (OTH) AF: 0.00700 AC: 210 AN: 30012

GnomAD4 genome AF: 0.0271 AC: 4103 AN: 151264 Hom.: 364 Cov.: 31 AF XY: 0.0255 AC XY: 1883 AN XY: 73930

African (AFR) AF: 0.0946 AC: 3870 AN: 40914

American (AMR) AF: 0.00952 AC: 145 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000590 AC: 40 AN: 67828

Other (OTH) AF: 0.0196 AC: 41 AN: 2088

Alfa AF: 0.0252 Hom.: 24

Bravo AF: 0.0321

Asia WGS AF: 0.00579 AC: 20 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.43
PhyloP100		-0.39
PromoterAI		-0.0059	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1080993; hg19: chr22-42526969;