22-42129180-A-T

Position:

• chr22-42129180-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000106.6(CYP2D6):​c.358T>A​(p.Phe120Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000499 in 1,604,188 control chromosomes in the GnomAD database, including 30 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F120L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00050 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (23 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.01

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008674651).
• BS2: High AC in GnomAd4 at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D6	NM_000106.6	c.358T>A	p.Phe120Ile	missense_variant	3/9	ENST00000645361.2
CYP2D6	NM_001025161.3	c.353-236T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2	c.358T>A	p.Phe120Ile	missense_variant	3/9		NM_000106.6	P1
NDUFA6-DT	ENST00000439129.5	n.1718+3773A>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000502 AC: 76 AN: 151398 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00716

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000482

GnomAD3 exomes AF: 0.00165 AC: 396 AN: 239358 Hom.: 12 AF XY: 0.00155 AC XY: 203 AN XY: 131082

Gnomad AFR exome AF: 0.000136

Gnomad AMR exome AF: 0.00461

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0109

Gnomad SAS exome AF: 0.000460

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000218

Gnomad OTH exome AF: 0.000847

GnomAD4 exome AF: 0.000499 AC: 725 AN: 1452678 Hom.: 23 Cov.: 37 AF XY: 0.000487 AC XY: 352 AN XY: 722984

Gnomad4 AFR exome AF: 0.0000900

Gnomad4 AMR exome AF: 0.00395

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00902

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.0000213

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.000482

GnomAD4 genome AF: 0.000502 AC: 76 AN: 151510 Hom.: 7 Cov.: 33 AF XY: 0.000567 AC XY: 42 AN XY: 74072

Gnomad4 AFR AF: 0.000146

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00718

Gnomad4 SAS AF: 0.000418

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000148

Gnomad4 OTH AF: 0.000477

Alfa AF: 0.000379 Hom.: 1

Bravo AF: 0.000907

ESP6500AA AF: 0.000493 AC: 2

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00133 AC: 160

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.0090
DANN	Benign	0.68
DEOGEN2	Benign	0.0010	T;T;T;T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0032	N
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.0087	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.85	N;N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.57	T
Vest4		0.17, 0.15
MVP		0.13
MPC		0.16
ClinPred		0.0031	T
GERP RS		-8.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.17
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1135822; hg19: chr22-42525182; COSMIC: COSV62244165; COSMIC: COSV62244165;