22-42126944-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000106.6(CYP2D6):c.1222G>A(p.Val408Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 151,420 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (6 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -1.02

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0302369).
• BS2: High AC in GnomAd at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D6	NM_000106.6	c.1222G>A	p.Val408Ile	missense_variant	8/9	ENST00000645361.2
CYP2D6	NM_001025161.3	c.1069G>A	p.Val357Ile	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2	c.1222G>A	p.Val408Ile	missense_variant	8/9		NM_000106.6	P1
NDUFA6-DT	ENST00000439129.5	n.1718+1537C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000370 AC: 56 AN: 151308 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000513

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000921

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.00241

GnomAD3 exomes AF: 0.000327 AC: 75 AN: 229322 Hom.: 1 AF XY: 0.000315 AC XY: 39 AN XY: 123756

Gnomad AFR exome AF: 0.000844

Gnomad AMR exome AF: 0.000704

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.0000581

Gnomad SAS exome AF: 0.000142

Gnomad FIN exome AF: 0.0000489

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.000873

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000309 AC: 451 AN: 1458222 Hom.: 6 Cov.: 39 AF XY: 0.000285 AC XY: 207 AN XY: 725222

Gnomad4 AFR exome AF: 0.000541

Gnomad4 AMR exome AF: 0.000585

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000187

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000302

Gnomad4 OTH exome AF: 0.000664

GnomAD4 genome AF: 0.000370 AC: 56 AN: 151420 Hom.: 1 Cov.: 31 AF XY: 0.000270 AC XY: 20 AN XY: 73994

Gnomad4 AFR AF: 0.000511

Gnomad4 AMR AF: 0.000920

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000192

Gnomad4 OTH AF: 0.00239

Alfa AF: 0.000388 Hom.: 0

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000257 AC: 31

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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	0.086
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	0.39
Dann	Benign	0.78
DEOGEN2	Benign	0.0010	T;T;T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.049	N
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.030	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
Vest4		0.12, 0.18, 0.19
MVP		0.22
MPC		0.089
ClinPred		0.0019	T
GERP RS		-5.9
Varity_R		0.044
gMVP		0.23

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: rs78762568; hg19: chr22-42522946; COSMIC: COSV62242887; COSMIC: COSV62242887;