rs16947

chr22-42127941-G-Achr22-42127941-G-Cchr22-42127941-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000106.6(CYP2D6):c.886C>T(p.Arg296Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 1,610,098 control chromosomes in the GnomAD database, including 108,422 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.39 (13067 hom., cov: 32)
  • Exomes 𝑓: 0.34 (95355 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.921

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008255243).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D6	NM_000106.6	c.886C>T	p.Arg296Cys	missense_variant	6/9	ENST00000645361.2
CYP2D6	NM_001025161.3	c.733C>T	p.Arg245Cys	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2	c.886C>T	p.Arg296Cys	missense_variant	6/9		NM_000106.6	P1
NDUFA6-DT	ENST00000439129.5	n.1718+2534G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58085 AN: 150702 Hom.: 13023 Cov.: 32

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.382

GnomAD4 exome AF: 0.336 AC: 490905 AN: 1459282 Hom.: 95355 Cov.: 56 AF XY: 0.339 AC XY: 245894 AN XY: 725958

Gnomad4 AFR exome AF: 0.527

Gnomad4 AMR exome AF: 0.285

Gnomad4 ASJ exome AF: 0.406

Gnomad4 EAS exome AF: 0.144

Gnomad4 SAS exome AF: 0.384

Gnomad4 FIN exome AF: 0.387

Gnomad4 NFE exome AF: 0.330

Gnomad4 OTH exome AF: 0.354

GnomAD4 genome AF: 0.386 AC: 58174 AN: 150816 Hom.: 13067 Cov.: 32 AF XY: 0.386 AC XY: 28466 AN XY: 73670

Gnomad4 AFR AF: 0.518

Gnomad4 AMR AF: 0.344

Gnomad4 ASJ AF: 0.394

Gnomad4 EAS AF: 0.148

Gnomad4 SAS AF: 0.382

Gnomad4 FIN AF: 0.389

Gnomad4 NFE AF: 0.335

Gnomad4 OTH AF: 0.378

Alfa AF: 0.322 Hom.: 2728

Bravo AF: 0.386

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_noAF	Benign	-0.92
Cadd	Benign	15
DEOGEN2	Benign	0.017	T;T;T;T;.
MetaRNN	Benign	0.0083	T;T;T;T;T
Vest4		0.17, 0.18, 0.19
gMVP		0.61

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs16947; hg19: chr22-42523943;