22-42129770-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM5BP4_StrongBS2

The NM_000106.6(CYP2D6):​c.320C>A​(p.Thr107Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,608,900 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. T107I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00079 ( 3 hom., cov: 32)
Exomes 𝑓: 0.00018 ( 13 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.91
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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr22-42129770-G-A is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.006817639).
BS2
High AC in GnomAd4 at 120 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CYP2D6NM_000106.6 linkuse as main transcriptc.320C>A p.Thr107Asn missense_variant 2/9 ENST00000645361.2 NP_000097.3
CYP2D6NM_001025161.3 linkuse as main transcriptc.320C>A p.Thr107Asn missense_variant 2/8 NP_001020332.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CYP2D6ENST00000645361.2 linkuse as main transcriptc.320C>A p.Thr107Asn missense_variant 2/9 NM_000106.6 ENSP00000496150 P1P10635-1
NDUFA6-DTENST00000439129.5 linkuse as main transcriptn.1718+4363G>T intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.000793
AC:
120
AN:
151272
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000244
Gnomad AMI
AF:
0.0336
Gnomad AMR
AF:
0.00507
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000194
Gnomad SAS
AF:
0.000625
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.000480
GnomAD3 exomes
AF:
0.000164
AC:
40
AN:
244170
Hom.:
6
AF XY:
0.000142
AC XY:
19
AN XY:
133408
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000915
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000328
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000547
Gnomad OTH exome
AF:
0.000333
GnomAD4 exome
AF:
0.000178
AC:
260
AN:
1457518
Hom.:
13
Cov.:
33
AF XY:
0.000165
AC XY:
120
AN XY:
725176
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.00393
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.000174
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000550
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.000793
AC:
120
AN:
151382
Hom.:
3
Cov.:
32
AF XY:
0.000933
AC XY:
69
AN XY:
73972
show subpopulations
Gnomad4 AFR
AF:
0.0000244
Gnomad4 AMR
AF:
0.00506
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.000626
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.000475
ExAC
AF:
0.000827
AC:
100
EpiCase
AF:
0.00
EpiControl
AF:
0.0000594

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.62
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
0.0030
DANN
Benign
0.55
DEOGEN2
Benign
0.0011
T;T;T;T;.
Eigen
Benign
-2.2
Eigen_PC
Benign
-2.2
FATHMM_MKL
Benign
0.0021
N
LIST_S2
Benign
0.12
.;.;T;T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.0068
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.025
N;N;N;.;N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-0.26
.;.;N;.;N
REVEL
Benign
0.14
Sift
Benign
0.31
.;.;T;.;T
Sift4G
Benign
0.22
.;.;T;T;T
Vest4
0.12, 0.13, 0.12
MutPred
0.52
Gain of relative solvent accessibility (P = 0.0905);Gain of relative solvent accessibility (P = 0.0905);Gain of relative solvent accessibility (P = 0.0905);.;Gain of relative solvent accessibility (P = 0.0905);
MVP
0.52
MPC
0.13
ClinPred
0.040
T
GERP RS
-1.7
Varity_R
0.19
gMVP
0.72

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28371706; hg19: chr22-42525772; API