22-42126611-C-G

Position:

• chr22-42126611-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000106.6(CYP2D6):​c.1457G>C​(p.Ser486Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 1,604,654 control chromosomes in the GnomAD database, including 260,369 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.58 (26496 hom., cov: 30)
  • Exomes 𝑓: 0.55 (233873 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Benign; other criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.805

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]

CYP2D6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069460273).
• BP6: Variant 22-42126611-C-G is Benign according to our data. Variant chr22-42126611-C-G is described in ClinVar as [Benign, other]. Clinvar id is 242701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-42126611-C-G is described in Lovd as [Benign]. Variant chr22-42126611-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.1457G>C	p.Ser486Thr	missense_variant	9/9	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.1304G>C	p.Ser435Thr	missense_variant	8/8		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.1457G>C	p.Ser486Thr	missense_variant	9/9		NM_000106.6	ENSP00000496150.1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 86472 AN: 149980 Hom.: 26459 Cov.: 30

Gnomad AFR AF: 0.643

Gnomad AMI AF: 0.528

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.646

Gnomad EAS AF: 0.689

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.559

Gnomad OTH AF: 0.564

GnomAD4 exome AF: 0.552 AC: 802703 AN: 1454562 Hom.: 233873 Cov.: 71 AF XY: 0.552 AC XY: 399578 AN XY: 723380

Gnomad4 AFR exome AF: 0.653

Gnomad4 AMR exome AF: 0.412

Gnomad4 ASJ exome AF: 0.659

Gnomad4 EAS exome AF: 0.623

Gnomad4 SAS exome AF: 0.541

Gnomad4 FIN exome AF: 0.507

Gnomad4 NFE exome AF: 0.551

Gnomad4 OTH exome AF: 0.567

GnomAD4 genome AF: 0.577 AC: 86546 AN: 150092 Hom.: 26496 Cov.: 30 AF XY: 0.572 AC XY: 41940 AN XY: 73304

Gnomad4 AFR AF: 0.643

Gnomad4 AMR AF: 0.490

Gnomad4 ASJ AF: 0.646

Gnomad4 EAS AF: 0.688

Gnomad4 SAS AF: 0.551

Gnomad4 FIN AF: 0.502

Gnomad4 NFE AF: 0.559

Gnomad4 OTH AF: 0.558

Alfa AF: 0.574 Hom.: 4303

Bravo AF: 0.578

ClinVar

Significance: Benign; other

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	- -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 06, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 27, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.028
DEOGEN2	Benign	0.0013	T;T;T;T;.
LIST_S2	Benign	0.0033	.;.;T;T;T
MetaRNN	Benign	0.0069	T;T;T;T;T
Sift4G	Benign	0.78	.;.;T;T;T
Vest4		0.11, 0.10, 0.14
gMVP		0.50

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1135840; hg19: chr22-42522613;