22-42130715-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000106.6(CYP2D6):​c.77G>A​(p.Arg26His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,602,016 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. R26C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0058 ( 50 hom., cov: 31)
Exomes 𝑓: 0.0011 ( 64 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

3
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.958

Publications

25 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]
NDUFA6-DT (HGNC:45273): (NDUFA6 divergent transcript)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0043866336).
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00585 (884/151146) while in subpopulation AFR AF = 0.0189 (773/40922). AF 95% confidence interval is 0.0178. There are 50 homozygotes in GnomAd4. There are 431 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
BS2
High AC in GnomAd4 at 884 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYP2D6NM_000106.6 linkc.77G>A p.Arg26His missense_variant Exon 1 of 9 ENST00000645361.2 NP_000097.3 P10635-1C1ID52Q5Y7H2
CYP2D6NM_001025161.3 linkc.77G>A p.Arg26His missense_variant Exon 1 of 8 NP_001020332.2 P10635-2Q5Y7H2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYP2D6ENST00000645361.2 linkc.77G>A p.Arg26His missense_variant Exon 1 of 9 NM_000106.6 ENSP00000496150.1 P10635-1

Frequencies

GnomAD3 genomes
AF:
0.00587
AC:
886
AN:
151032
Hom.:
50
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0190
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00257
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00691
Gnomad FIN
AF:
0.0000944
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000428
Gnomad OTH
AF:
0.00434
GnomAD2 exomes
AF:
0.00223
AC:
524
AN:
235250
AF XY:
0.00203
show subpopulations
Gnomad AFR exome
AF:
0.0176
Gnomad AMR exome
AF:
0.00151
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000506
Gnomad FIN exome
AF:
0.000246
Gnomad NFE exome
AF:
0.000361
Gnomad OTH exome
AF:
0.00121
GnomAD4 exome
AF:
0.00106
AC:
1543
AN:
1450870
Hom.:
64
Cov.:
33
AF XY:
0.00111
AC XY:
801
AN XY:
720880
show subpopulations
African (AFR)
AF:
0.0174
AC:
576
AN:
33170
American (AMR)
AF:
0.00202
AC:
88
AN:
43592
Ashkenazi Jewish (ASJ)
AF:
0.0000385
AC:
1
AN:
25976
East Asian (EAS)
AF:
0.000356
AC:
14
AN:
39356
South Asian (SAS)
AF:
0.00493
AC:
417
AN:
84508
European-Finnish (FIN)
AF:
0.0000190
AC:
1
AN:
52666
Middle Eastern (MID)
AF:
0.000530
AC:
3
AN:
5662
European-Non Finnish (NFE)
AF:
0.000285
AC:
315
AN:
1106100
Other (OTH)
AF:
0.00214
AC:
128
AN:
59840
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.484
Heterozygous variant carriers
0
87
174
262
349
436
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
30
60
90
120
150
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00585
AC:
884
AN:
151146
Hom.:
50
Cov.:
31
AF XY:
0.00583
AC XY:
431
AN XY:
73866
show subpopulations
African (AFR)
AF:
0.0189
AC:
773
AN:
40922
American (AMR)
AF:
0.00257
AC:
39
AN:
15202
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5146
South Asian (SAS)
AF:
0.00692
AC:
33
AN:
4772
European-Finnish (FIN)
AF:
0.0000944
AC:
1
AN:
10596
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.000428
AC:
29
AN:
67742
Other (OTH)
AF:
0.00430
AC:
9
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
38
76
113
151
189
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.123
Hom.:
3254
Bravo
AF:
0.00646
ESP6500AA
AF:
0.0168
AC:
74
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.00249
AC:
302

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.21
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.022
T;T;T;T;.
Eigen
Benign
-0.63
Eigen_PC
Benign
-0.57
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.74
.;.;T;T;T
MetaRNN
Benign
0.0044
T;T;T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
1.0
L;L;L;.;L
PhyloP100
0.96
PrimateAI
Benign
0.45
T
PROVEAN
Uncertain
-3.6
.;.;D;.;D
REVEL
Benign
0.26
Sift
Benign
0.090
.;.;T;.;T
Sift4G
Uncertain
0.059
.;.;T;T;T
Vest4
0.25, 0.33, 0.24
MVP
0.52
MPC
0.16
ClinPred
0.032
T
GERP RS
2.4
PromoterAI
0.023
Neutral
Varity_R
0.090
gMVP
0.46
Mutation Taster
=97/3
polymorphism

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

Other links and lift over

dbSNP: rs28371696; hg19: chr22-42526717; COSMIC: COSV62244918; COSMIC: COSV62244918; API