NM_000106.6:c.1324G>A

Variant names:

• chr22-42126744-C-T
• rs1314121486
• NM_000106.6:c.1324G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000106.6(CYP2D6):​c.1324G>A​(p.Ala442Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,551,552 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000019 (1 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.36
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2658648).
• BS2: High AC in GnomAdExome4 at 27 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000106.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	NM_000106.6	MANE Select	c.1324G>A	p.Ala442Thr	missense	Exon 9 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.1171G>A	p.Ala391Thr	missense	Exon 8 of 8	NP_001020332.2	P10635-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	ENST00000645361.2	MANE Select	c.1324G>A	p.Ala442Thr	missense	Exon 9 of 9	ENSP00000496150.1	P10635-1
	CYP2D6	ENST00000359033.4	TSL:1	c.1171G>A	p.Ala391Thr	missense	Exon 8 of 8	ENSP00000351927.4	P10635-2
	CYP2D6	ENST00000360124.10	TSL:1	n.*399G>A		non_coding_transcript_exon	Exon 8 of 8	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150186 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000202 AC: 3 AN: 148164 AF XY: 0.0000127

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000533

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000193 AC: 27 AN: 1401366 Hom.: 1 Cov.: 39 AF XY: 0.0000217 AC XY: 15 AN XY: 691730

African (AFR) AF: 0.00 AC: 0 AN: 31802

American (AMR) AF: 0.00 AC: 0 AN: 35920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 36272

South Asian (SAS) AF: 0.00 AC: 0 AN: 79452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4632

European-Non Finnish (NFE) AF: 0.0000231 AC: 25 AN: 1080540

Other (OTH) AF: 0.0000345 AC: 2 AN: 58002

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150186 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 73320

African (AFR) AF: 0.00 AC: 0 AN: 40422

American (AMR) AF: 0.00 AC: 0 AN: 15112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.00 AC: 0 AN: 4724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67538

Other (OTH) AF: 0.00 AC: 0 AN: 2044

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.59
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-1.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.064	T
Sift4G	Benign	0.17	T
Vest4		0.070
MutPred		0.49		Gain of phosphorylation at A442 (P = 0.0526)
MVP		0.39
MPC		0.14
ClinPred		0.13	T
GERP RS		-7.6
Varity_R		0.088
gMVP		0.28
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs1314121486; hg19: chr22-42522746;