22-42130692-G-C

Position:

• chr22-42130692-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000106.6(CYP2D6):​c.100C>G​(p.Pro34Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. P34S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.37

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]

CYP2D6 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-42130692-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.100C>G	p.Pro34Ala	missense_variant	1/9	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.100C>G	p.Pro34Ala	missense_variant	1/8		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.100C>G	p.Pro34Ala	missense_variant	1/9		NM_000106.6	ENSP00000496150.1
CYP2D6	ENST00000359033.4	c.100C>G	p.Pro34Ala	missense_variant	1/8	1		ENSP00000351927.4
CYP2D6	ENST00000488442.1	n.122C>G		non_coding_transcript_exon_variant	1/8	5
NDUFA6-DT	ENST00000439129.5	n.1718+5285G>C		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	T;T;T;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;.;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	4.1	H;H;H;.;H
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-7.4	.;.;D;.;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	.;.;D;.;D
Sift4G	Uncertain	0.0060	.;.;D;D;D
Vest4		0.55, 0.60, 0.66
MutPred		0.73		Loss of glycosylation at P34 (P = 0.0043);Loss of glycosylation at P34 (P = 0.0043);Loss of glycosylation at P34 (P = 0.0043);.;Loss of glycosylation at P34 (P = 0.0043);
MVP		0.90
MPC		0.52
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.54
gMVP		0.76

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: rs1065852; hg19: chr22-42526694;