22-42127856-T-G

Position:

• chr22-42127856-T-G

Variant summary

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

The NM_000106.6(CYP2D6):​c.971A>C​(p.His324Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000782 in 1,610,966 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00056 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (31 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Likely benign; other criteria provided, multiple submitters, no conflicts B:1 O:1
• Conservation: PhyloP100: 5.92

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=0.020407856).
• BS2: High AC in GnomAd4 at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D6	NM_000106.6	c.971A>C	p.His324Pro	missense_variant	6/9	ENST00000645361.2
CYP2D6	NM_001025161.3	c.818A>C	p.His273Pro	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2	c.971A>C	p.His324Pro	missense_variant	6/9		NM_000106.6	P1
NDUFA6-DT	ENST00000439129.5	n.1718+2449T>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000569 AC: 86 AN: 151196 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00897

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000443

Gnomad OTH AF: 0.000967

GnomAD3 exomes AF: 0.00129 AC: 325 AN: 251012 Hom.: 14 AF XY: 0.00178 AC XY: 242 AN XY: 135710

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00818

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000511

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000804 AC: 1174 AN: 1459654 Hom.: 31 Cov.: 36 AF XY: 0.00106 AC XY: 771 AN XY: 726114

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00775

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000385

Gnomad4 OTH exome AF: 0.000796

GnomAD4 genome AF: 0.000562 AC: 85 AN: 151312 Hom.: 2 Cov.: 33 AF XY: 0.000716 AC XY: 53 AN XY: 73972

Gnomad4 AFR AF: 0.0000731

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00898

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000443

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000593 Hom.: 1

Bravo AF: 0.000393

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00134 AC: 163

EpiCase AF: 0.000764

EpiControl AF: 0.000771

ClinVar

Significance: Likely benign; other

Submissions summary: Benign:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 06, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.063	T;T;T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	.;.;T;T;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.020	T;T;T;T;T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	4.0	H;H;H;.;.
MutationTaster	Benign	0.91	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.7	.;.;D;.;D
REVEL	Benign	0.28
Sift	Uncertain	0.0020	.;.;D;.;D
Sift4G	Uncertain	0.030	.;.;D;D;D
Vest4		0.59, 0.59, 0.57
MVP		0.84
MPC		0.65
ClinPred		0.24	T
GERP RS		3.4
Varity_R		0.79
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs5030867; hg19: chr22-42523858;