rs267608313

chr22-42130719-G-Achr22-42130719-G-Cchr22-42130719-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000106.6(CYP2D6):c.73C>T(p.Arg25Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,600,380 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.240

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D6	NM_000106.6	c.73C>T	p.Arg25Trp	missense_variant	1/9	ENST00000645361.2
CYP2D6	NM_001025161.3	c.73C>T	p.Arg25Trp	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2	c.73C>T	p.Arg25Trp	missense_variant	1/9		NM_000106.6	P1
NDUFA6-DT	ENST00000439129.5	n.1718+5312G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151030 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000214 AC: 5 AN: 233150 Hom.: 0 AF XY: 0.00000792 AC XY: 1 AN XY: 126210

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000565

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000289

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000200 AC: 29 AN: 1449350 Hom.: 0 Cov.: 33 AF XY: 0.0000167 AC XY: 12 AN XY: 719916

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000231

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000229

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000154

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151030 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73740

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000248 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.032	T;T;T;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.078	N
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.48	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.97	L;L;L;.;L
MutationTaster	Benign	0.58	D;D;D
PrimateAI	Benign	0.46	T
Vest4		0.21, 0.25, 0.23
MutPred		0.64		Loss of disorder (P = 0.0682);Loss of disorder (P = 0.0682);Loss of disorder (P = 0.0682);.;Loss of disorder (P = 0.0682);
MVP		0.61
MPC		0.17
ClinPred		0.37	T
GERP RS		-0.041
Varity_R		0.17
gMVP		0.54

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: rs267608313; hg19: chr22-42526721; COSMIC: COSV100637261; COSMIC: COSV100637261;