dbSNP rs5030862: CYP2D6:p.Gly42Trp (chr22-42130668-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000106.6(CYP2D6):c.124G>T(p.Gly42Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G42R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CYP2D6
NM_000106.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.227

Publications

0 publications found

Variant links:

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 links:

NDUFA6-DT (HGNC:45273): (NDUFA6 divergent transcript)

NDUFA6-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000106.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	NM_000106.6	MANE Select	c.124G>T	p.Gly42Trp	missense	Exon 1 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.124G>T	p.Gly42Trp	missense	Exon 1 of 8	NP_001020332.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CYP2D6	ENST00000645361.2	MANE Select	c.124G>T	p.Gly42Trp	missense	Exon 1 of 9	ENSP00000496150.1
CYP2D6	ENST00000359033.4	TSL:1	c.124G>T	p.Gly42Trp	missense	Exon 1 of 8	ENSP00000351927.4
CYP2D6	ENST00000360124.10	TSL:1	n.124G>T		non_coding_transcript_exon	Exon 1 of 8	ENSP00000353241.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1457908

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725100

African (AFR)

AF:

0.00

AC:

AN:

33316

American (AMR)

AF:

0.00

AC:

AN:

44452

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39562

South Asian (SAS)

AF:

0.00

AC:

AN:

85742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109552

Other (OTH)

AF:

0.00

AC:

AN:

60168

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0044

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.019

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.0089

MetaRNN

Uncertain

0.51

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

-0.23

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.13

Sift

Uncertain

0.021

Sift4G

Uncertain

0.018

Vest4

0.36

MutPred

0.48

Loss of disorder (P = 0.0127)

MVP

0.40

MPC

0.59

ClinPred

0.81

GERP RS

0.077

PromoterAI

0.022

Neutral

(source)

Varity_R

0.12

gMVP

0.77

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over