rs28371706

chr22-42129770-G-Achr22-42129770-G-Cchr22-42129770-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000106.6(CYP2D6):c.320C>T(p.Thr107Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,609,412 control chromosomes in the GnomAD database, including 2,087 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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 0.052 (1019 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (1068 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Likely benign; other criteria provided, multiple submitters, no conflicts B:1 O:1
• Conservation: PhyloP100: -2.91

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049679875).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D6	NM_000106.6	c.320C>T	p.Thr107Ile	missense_variant	2/9	ENST00000645361.2
CYP2D6	NM_001025161.3	c.320C>T	p.Thr107Ile	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2	c.320C>T	p.Thr107Ile	missense_variant	2/9		NM_000106.6	P1
NDUFA6-DT	ENST00000439129.5	n.1718+4363G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0518 AC: 7830 AN: 151262 Hom.: 1010 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.0379

GnomAD3 exomes AF: 0.0141 AC: 3431 AN: 244170 Hom.: 415 AF XY: 0.0109 AC XY: 1450 AN XY: 133408

Gnomad AFR exome AF: 0.185

Gnomad AMR exome AF: 0.00717

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.000191

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00799

GnomAD4 exome AF: 0.00619 AC: 9031 AN: 1458040 Hom.: 1068 Cov.: 33 AF XY: 0.00544 AC XY: 3948 AN XY: 725406

Gnomad4 AFR exome AF: 0.196

Gnomad4 AMR exome AF: 0.00920

Gnomad4 ASJ exome AF: 0.0167

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.000192

Gnomad4 NFE exome AF: 0.000599

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.0519 AC: 7849 AN: 151372 Hom.: 1019 Cov.: 32 AF XY: 0.0496 AC XY: 3672 AN XY: 73974

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00114

Gnomad4 OTH AF: 0.0375

Alfa AF: 0.0131 Hom.: 47

Bravo AF: 0.0583

ESP6500AA AF: 0.169 AC: 741

ESP6500EA AF: 0.00175 AC: 15

ExAC AF: 0.0178 AC: 2149

EpiCase AF: 0.00186

EpiControl AF: 0.00190

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	Benign	0.25
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	0.0060
Dann	Benign	0.81
DEOGEN2	Benign	0.00096	T;T;T;T;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0040	N
MetaRNN	Benign	0.0050	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.070	N;N;N;.;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.46	T
Vest4		0.069, 0.11, 0.085
MPC		0.12
ClinPred		0.0065	T
GERP RS		-1.7
Varity_R		0.16
gMVP		0.66

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: rs28371706; hg19: chr22-42525772; COSMIC: COSV62243897; COSMIC: COSV62243897;