22-42129170-C-T

Position:

• chr22-42129170-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000106.6(CYP2D6):​c.368G>A​(p.Arg123His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000963 in 1,454,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. R123L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (1 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.31

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)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11875817).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D6	NM_000106.6	c.368G>A	p.Arg123His	missense_variant	3/9	ENST00000645361.2
CYP2D6	NM_001025161.3	c.353-226G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2	c.368G>A	p.Arg123His	missense_variant	3/9		NM_000106.6	P1
NDUFA6-DT	ENST00000439129.5	n.1718+3763C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000415 AC: 1 AN: 240814 Hom.: 0 AF XY: 0.00000759 AC XY: 1 AN XY: 131724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000963 AC: 14 AN: 1454146 Hom.: 1 Cov.: 37 AF XY: 0.00000829 AC XY: 6 AN XY: 723684

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000830 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	1.0
DANN	Benign	0.88
DEOGEN2	Benign	0.0011	T;T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.74	.;.;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.84	L;L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.24	.;.;N;D
REVEL	Benign	0.050
Sift	Benign	0.46	.;.;T;D
Sift4G	Benign	0.20	.;.;T;T
Vest4		0.096, 0.099
MutPred		0.62		Loss of MoRF binding (P = 0.0082);Loss of MoRF binding (P = 0.0082);Loss of MoRF binding (P = 0.0082);.;
MVP		0.39
MPC		0.14
ClinPred		0.039	T
GERP RS		0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.095
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs373000587; hg19: chr22-42525172; COSMIC: COSV62246166; COSMIC: COSV62246166;