chr22-42130834-A-AC

Variant names:

• chr22-42130834-A-AC
• rs28371695
• ENST00000359033.4:c.-44dupG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000359033.4(CYP2D6):​c.-44dupG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00762 in 1,514,736 control chromosomes in the GnomAD database, including 1,162 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.039 (619 hom., cov: 31)
  • Exomes 𝑓: 0.0042 (543 hom.)
• Consequence: CYP2D6 ENST00000359033.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 1 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359033.4. 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.-44_-43insG		upstream_gene	N/A	NP_000097.3
	CYP2D6	NM_001025161.3		c.-44_-43insG		upstream_gene	N/A	NP_001020332.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	ENST00000359033.4	TSL:1	c.-44dupG		5_prime_UTR	Exon 1 of 8	ENSP00000351927.4
	NDUFA6-DT	ENST00000439129.5	TSL:5	n.1719-5360dupC		intron	N/A
	CYP2D6	ENST00000645361.2	MANE Select	c.-44dupG		upstream_gene	N/A	ENSP00000496150.1

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5864 AN: 150742 Hom.: 619 Cov.: 31

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000630

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000591

Gnomad OTH AF: 0.0333

GnomAD2 exomes AF: 0.00937 AC: 1476 AN: 157586 AF XY: 0.00694

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.00732

Gnomad ASJ exome AF: 0.00117

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000672

Gnomad OTH exome AF: 0.00478

GnomAD4 exome AF: 0.00416 AC: 5668 AN: 1363880 Hom.: 543 Cov.: 28 AF XY: 0.00354 AC XY: 2387 AN XY: 674698

African (AFR) AF: 0.141 AC: 4290 AN: 30486

American (AMR) AF: 0.00805 AC: 289 AN: 35904

Ashkenazi Jewish (ASJ) AF: 0.000996 AC: 25 AN: 25096

East Asian (EAS) AF: 0.00 AC: 0 AN: 36120

South Asian (SAS) AF: 0.000356 AC: 28 AN: 78596

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49208

Middle Eastern (MID) AF: 0.00674 AC: 32 AN: 4748

European-Non Finnish (NFE) AF: 0.000391 AC: 409 AN: 1046934

Other (OTH) AF: 0.0105 AC: 594 AN: 56788

GnomAD4 genome AF: 0.0389 AC: 5871 AN: 150856 Hom.: 619 Cov.: 31 AF XY: 0.0367 AC XY: 2708 AN XY: 73712

African (AFR) AF: 0.136 AC: 5544 AN: 40742

American (AMR) AF: 0.0135 AC: 205 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000631 AC: 3 AN: 4756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

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

European-Non Finnish (NFE) AF: 0.000591 AC: 40 AN: 67698

Other (OTH) AF: 0.0330 AC: 69 AN: 2092

Alfa AF: 0.0211 Hom.: 51

Bravo AF: 0.0442

Asia WGS AF: 0.00985 AC: 35 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=300/0	polymorphism (auto)

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: rs28371695; hg19: chr22-42526836;