rs28371702

chr22-42129950-A-Cchr22-42129950-A-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.181-41T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 130,546 control chromosomes in the GnomAD database, including 24,907 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 (24907 hom., cov: 16)
  • Exomes 𝑓: 0.55 (218680 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP2D6 NM_000106.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.36

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=-0.86).
• BP6: Variant 22-42129950-A-C is Benign according to our data. Variant chr22-42129950-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D6	NM_000106.6	c.181-41T>G		intron_variant		ENST00000645361.2
CYP2D6	NM_001025161.3	c.181-41T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2	c.181-41T>G		intron_variant			NM_000106.6	P1
NDUFA6-DT	ENST00000439129.5	n.1718+4543A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.605 AC: 78874 AN: 130452 Hom.: 24871 Cov.: 16

Gnomad AFR AF: 0.738

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.645

Gnomad EAS AF: 0.712

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.632

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.590

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.554 AC: 747831 AN: 1348904 Hom.: 218680 Cov.: 32 AF XY: 0.555 AC XY: 369697 AN XY: 666704

Gnomad4 AFR exome AF: 0.750

Gnomad4 AMR exome AF: 0.432

Gnomad4 ASJ exome AF: 0.656

Gnomad4 EAS exome AF: 0.627

Gnomad4 SAS exome AF: 0.542

Gnomad4 FIN exome AF: 0.504

Gnomad4 NFE exome AF: 0.549

Gnomad4 OTH exome AF: 0.575

GnomAD4 genome AF: 0.605 AC: 78946 AN: 130546 Hom.: 24907 Cov.: 16 AF XY: 0.602 AC XY: 37797 AN XY: 62832

Gnomad4 AFR AF: 0.738

Gnomad4 AMR AF: 0.504

Gnomad4 ASJ AF: 0.645

Gnomad4 EAS AF: 0.711

Gnomad4 SAS AF: 0.555

Gnomad4 FIN AF: 0.507

Gnomad4 NFE AF: 0.560

Gnomad4 OTH AF: 0.583

Alfa AF: 0.528 Hom.: 3024

Bravo AF: 0.612

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.6

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs28371702; hg19: chr22-42525952;