rs28371717

chr22-42128308-C-Achr22-42128308-C-Gchr22-42128308-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000106.6(CYP2D6):c.709G>T(p.Ala237Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,610,552 control chromosomes in the GnomAD database, including 650 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0079 (38 hom., cov: 31)
  • Exomes 𝑓: 0.011 (612 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.594

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048805773).
• BP6: Variant 22-42128308-C-A is Benign according to our data. Variant chr22-42128308-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 513099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-42128308-C-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 1198 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D6	NM_000106.6	c.709G>T	p.Ala237Ser	missense_variant	5/9	ENST00000645361.2
CYP2D6	NM_001025161.3	c.556G>T	p.Ala186Ser	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2	c.709G>T	p.Ala237Ser	missense_variant	5/9		NM_000106.6	P1
NDUFA6-DT	ENST00000439129.5	n.1718+2901C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00794 AC: 1198 AN: 150866 Hom.: 38 Cov.: 31

Gnomad AFR AF: 0.00172

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.00448

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00421

Gnomad FIN AF: 0.00945

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.00726

GnomAD3 exomes AF: 0.00791 AC: 1984 AN: 250760 Hom.: 79 AF XY: 0.00805 AC XY: 1091 AN XY: 135550

Gnomad AFR exome AF: 0.00210

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00677

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00686

GnomAD4 exome AF: 0.0106 AC: 15514 AN: 1459572 Hom.: 612 Cov.: 35 AF XY: 0.0105 AC XY: 7600 AN XY: 726086

Gnomad4 AFR exome AF: 0.00180

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00628

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.00748

GnomAD4 genome AF: 0.00793 AC: 1198 AN: 150980 Hom.: 38 Cov.: 31 AF XY: 0.00793 AC XY: 585 AN XY: 73778

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00447

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00421

Gnomad4 FIN AF: 0.00945

Gnomad4 NFE AF: 0.0129

Gnomad4 OTH AF: 0.00718

Alfa AF: 0.0107 Hom.: 27

Bravo AF: 0.00694

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0101 AC: 87

ExAC AF: 0.00756 AC: 917

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 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

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

CYP2D6: BP4, BS1, BS2 -

Tramadol response Other:1

drug response, no assertion criteria provided

research

Bruce Budowle Laboratory, University of North Texas Health Science Center

Apr 28, 2018

- T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.41
Dann	Benign	0.88
DEOGEN2	Benign	0.0044	T;T;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.057	N
MetaRNN	Benign	0.0049	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.3	L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
Vest4		0.19, 0.22, 0.22
MVP		0.54
MPC		0.11
ClinPred		0.012	T
GERP RS		-6.5
Varity_R		0.16
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs28371717; hg19: chr22-42524310; COSMIC: COSV62244303; COSMIC: COSV62244303;