Genetic Variant CYP2D6:c.180+43C>A (chr22-42130569-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000106.6(CYP2D6):c.180+43C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 23)

Exomes 𝑓: 9.3e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CYP2D6
NM_000106.6 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00100

Publications

7 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (Cadd=1.0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6 link	c.180+43C>A		intron_variant	Intron 1 of 8	ENST00000645361.2	NP_000097.3	P10635-1C1ID52Q5Y7H2
CYP2D6	NM_001025161.3 link	c.180+43C>A		intron_variant	Intron 1 of 7		NP_001020332.2	P10635-2Q5Y7H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2 link	c.180+43C>A		intron_variant	Intron 1 of 8		NM_000106.6	ENSP00000496150.1		P10635-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

105184

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.32e-7

AC:

AN:

1072478

Hom.:

Cov.:

AF XY:

0.00000186

AC XY:

AN XY:

537954

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24292

American (AMR)

AF:

0.00

AC:

AN:

35262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20754

East Asian (EAS)

AF:

0.00

AC:

AN:

36418

South Asian (SAS)

AF:

0.00

AC:

AN:

67536

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3796

European-Non Finnish (NFE)

AF:

0.00000126

AC:

AN:

795234

Other (OTH)

AF:

0.00

AC:

AN:

45996

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

105184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

50762

African (AFR)

AF:

0.00

AC:

AN:

27768

American (AMR)

AF:

0.00

AC:

AN:

10706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2344

East Asian (EAS)

AF:

0.00

AC:

AN:

4558

South Asian (SAS)

AF:

0.00

AC:

AN:

2914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

182

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

48046

Other (OTH)

AF:

0.00

AC:

AN:

1378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

CADD

Benign

1.0

(source)

PhyloP100

0.0010

PromoterAI

0.0060

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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22-42130569-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over