rs28371699

Positions:

• chr22-42130482-C-A
• chr22-42130482-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000106.6(CYP2D6):​c.180+130G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 1,048,700 control chromosomes in the GnomAD database, including 175,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.60 (27620 hom., cov: 26)
  • Exomes 𝑓: 0.56 (147425 hom.)
• Consequence: CYP2D6 NM_000106.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0170

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 22-42130482-C-A is Benign according to our data. Variant chr22-42130482-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D6	NM_000106.6	c.180+130G>T		intron_variant		ENST00000645361.2
CYP2D6	NM_001025161.3	c.180+130G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2	c.180+130G>T		intron_variant			NM_000106.6	P1
NDUFA6-DT	ENST00000439129.5	n.1718+5075C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.598 AC: 85794 AN: 143570 Hom.: 27577 Cov.: 26

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.574

GnomAD4 exome AF: 0.557 AC: 504282 AN: 905022 Hom.: 147425 Cov.: 12 AF XY: 0.557 AC XY: 257850 AN XY: 463070

Gnomad4 AFR exome AF: 0.752

Gnomad4 AMR exome AF: 0.429

Gnomad4 ASJ exome AF: 0.652

Gnomad4 EAS exome AF: 0.617

Gnomad4 SAS exome AF: 0.541

Gnomad4 FIN exome AF: 0.495

Gnomad4 NFE exome AF: 0.556

Gnomad4 OTH exome AF: 0.578

GnomAD4 genome AF: 0.598 AC: 85878 AN: 143678 Hom.: 27620 Cov.: 26 AF XY: 0.592 AC XY: 41411 AN XY: 69926

Gnomad4 AFR AF: 0.739

Gnomad4 AMR AF: 0.491

Gnomad4 ASJ AF: 0.642

Gnomad4 EAS AF: 0.690

Gnomad4 SAS AF: 0.538

Gnomad4 FIN AF: 0.481

Gnomad4 NFE AF: 0.552

Gnomad4 OTH AF: 0.568

Alfa AF: 0.430 Hom.: 991

Bravo AF: 0.611

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.92

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs28371699; hg19: chr22-42526484;