chr22-42130482-C-A

Variant names:

• chr22-42130482-C-A
• rs28371699
• NM_000106.6:c.180+130G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 20 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=-0.84).
• 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 rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.180+130G>T		intron_variant	Intron 1 of 8	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.180+130G>T		intron_variant	Intron 1 of 7		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.180+130G>T		intron_variant	Intron 1 of 8		NM_000106.6	ENSP00000496150.1

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

African (AFR) AF: 0.752 AC: 16402 AN: 21818

American (AMR) AF: 0.429 AC: 14881 AN: 34686

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 14398 AN: 22088

East Asian (EAS) AF: 0.617 AC: 20974 AN: 33986

South Asian (SAS) AF: 0.541 AC: 36880 AN: 68224

European-Finnish (FIN) AF: 0.495 AC: 22883 AN: 46196

Middle Eastern (MID) AF: 0.582 AC: 2019 AN: 3468

European-Non Finnish (NFE) AF: 0.556 AC: 351760 AN: 632918

Other (OTH) AF: 0.578 AC: 24085 AN: 41638

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

African (AFR) AF: 0.739 AC: 28444 AN: 38484

American (AMR) AF: 0.491 AC: 7087 AN: 14444

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2170 AN: 3380

East Asian (EAS) AF: 0.690 AC: 3459 AN: 5012

South Asian (SAS) AF: 0.538 AC: 2389 AN: 4442

European-Finnish (FIN) AF: 0.481 AC: 4670 AN: 9700

Middle Eastern (MID) AF: 0.646 AC: 186 AN: 288

European-Non Finnish (NFE) AF: 0.552 AC: 35881 AN: 65052

Other (OTH) AF: 0.568 AC: 1136 AN: 2000

Alfa AF: 0.454 Hom.: 1187

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
PhyloP100		-0.017
PromoterAI		0.048	Neutral

Splicing

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

Other links and lift over

dbSNP: rs28371699; hg19: chr22-42526484;