rs267608319

chr22-42126749-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.1319G>A(p.Arg440His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,549,504 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R440C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00014 (5 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 0.319

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=0.06325573).
• BS2: High AC in GnomAd at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D6	NM_000106.6	c.1319G>A	p.Arg440His	missense_variant	9/9	ENST00000645361.2
CYP2D6	NM_001025161.3	c.1166G>A	p.Arg389His	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2	c.1319G>A	p.Arg440His	missense_variant	9/9		NM_000106.6	P1
NDUFA6-DT	ENST00000439129.5	n.1718+1342C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000387 AC: 58 AN: 150038 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00225

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000193

Gnomad OTH AF: 0.00196

GnomAD3 exomes AF: 0.000219 AC: 32 AN: 145816 Hom.: 1 AF XY: 0.000270 AC XY: 21 AN XY: 77670

Gnomad AFR exome AF: 0.000271

Gnomad AMR exome AF: 0.000554

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000458

Gnomad FIN exome AF: 0.000200

Gnomad NFE exome AF: 0.000200

Gnomad OTH exome AF: 0.000485

GnomAD4 exome AF: 0.000143 AC: 200 AN: 1399352 Hom.: 5 Cov.: 38 AF XY: 0.000155 AC XY: 107 AN XY: 690498

Gnomad4 AFR exome AF: 0.0000946

Gnomad4 AMR exome AF: 0.000614

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000378

Gnomad4 FIN exome AF: 0.000263

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.000466

GnomAD4 genome AF: 0.000386 AC: 58 AN: 150152 Hom.: 0 Cov.: 30 AF XY: 0.000436 AC XY: 32 AN XY: 73326

Gnomad4 AFR AF: 0.000124

Gnomad4 AMR AF: 0.00225

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000197

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000193

Gnomad4 OTH AF: 0.00194

Alfa AF: 0.000342 Hom.: 0

Bravo AF: 0.000616

ExAC AF: 0.0000420 AC: 4

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Other:1

drug response, no assertion criteria provided

not provided

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.018	T;T;T;T;.
Eigen	Benign	0.021
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.063	T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.4	M;M;M;.;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.48	T
Vest4		0.34, 0.37, 0.37
MutPred		0.69		Loss of methylation at R440 (P = 0.0071);Loss of methylation at R440 (P = 0.0071);Loss of methylation at R440 (P = 0.0071);.;.;
MVP		0.76
MPC		0.19
ClinPred		0.081	T
GERP RS		1.4
Varity_R		0.45
gMVP		0.48

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: rs267608319; hg19: chr22-42522751;