22-42129132-C-T

Position:

• chr22-42129132-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP5 BP4 BA1

The NM_000106.6(CYP2D6):​c.406G>A​(p.Val136Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,609,922 control chromosomes in the GnomAD database, including 523 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. V136V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.026 (357 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (166 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.89

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.

• PP5: Variant 22-42129132-C-T is Pathogenic according to our data. Variant chr22-42129132-C-T is described in Lovd as [Likely_pathogenic]. Variant chr22-42129132-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.002351731). . Strength limited to SUPPORTING due to the PP5.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.406G>A	p.Val136Met	missense_variant	3/9	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.353-188G>A		intron_variant			NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.406G>A	p.Val136Met	missense_variant	3/9		NM_000106.6	ENSP00000496150	P1
NDUFA6-DT	ENST00000439129.5	n.1718+3725C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3959 AN: 151462 Hom.: 357 Cov.: 33

Gnomad AFR AF: 0.0909

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00951

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000575

Gnomad OTH AF: 0.0179

GnomAD3 exomes AF: 0.00668 AC: 1640 AN: 245456 Hom.: 123 AF XY: 0.00502 AC XY: 671 AN XY: 133790

Gnomad AFR exome AF: 0.0951

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.00210

Gnomad EAS exome AF: 0.000504

Gnomad SAS exome AF: 0.000295

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000233

Gnomad OTH exome AF: 0.00284

GnomAD4 exome AF: 0.00265 AC: 3868 AN: 1458348 Hom.: 166 Cov.: 37 AF XY: 0.00227 AC XY: 1646 AN XY: 725544

Gnomad4 AFR exome AF: 0.0916

Gnomad4 AMR exome AF: 0.00464

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.000314

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000154

Gnomad4 OTH exome AF: 0.00560

GnomAD4 genome AF: 0.0262 AC: 3967 AN: 151574 Hom.: 357 Cov.: 33 AF XY: 0.0244 AC XY: 1808 AN XY: 74090

Gnomad4 AFR AF: 0.0908

Gnomad4 AMR AF: 0.00950

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000582

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000575

Gnomad4 OTH AF: 0.0177

Alfa AF: 0.00327 Hom.: 29

Bravo AF: 0.0307

ESP6500AA AF: 0.0877 AC: 356

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.00830 AC: 1003

Asia WGS AF: 0.00579 AC: 20 AN: 3468

EpiCase AF: 0.000273

EpiControl AF: 0.000238

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.35
DANN	Benign	0.93
DEOGEN2	Benign	0.0053	T;T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.85	.;.;D;D
MetaRNN	Benign	0.0024	T;T;T;T
MutationTaster	Benign	1.0	P;P;P
PROVEAN	Benign	-1.4	.;.;N;.
Sift	Benign	0.042	.;.;D;.
Sift4G	Uncertain	0.022	.;.;D;D
Vest4		0.16, 0.16
MVP		0.26
ClinPred		0.0070	T
GERP RS		-8.2
Varity_R		0.11
gMVP		0.44

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

Other links and lift over

dbSNP: rs61736512; hg19: chr22-42525134; COSMIC: COSV62243446; COSMIC: COSV62243446;