22-42128662-T-G

Variant names:

• chr22-42128662-T-G
• rs267608290
• NM_000106.6:c.666+122A>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000106.6(CYP2D6):​c.666+122A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000391 in 1,165,106 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0017 (7 hom., cov: 31)
  • Exomes 𝑓: 0.00019 (9 hom.)
• Consequence: CYP2D6 NM_000106.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.620
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS2: High AC in GnomAd4 at 261 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.666+122A>C		intron	N/A	NP_000097.3
	CYP2D6	NM_001025161.3		c.513+122A>C		intron	N/A	NP_001020332.2	P10635-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	ENST00000645361.2	MANE Select	c.666+122A>C		intron	N/A	ENSP00000496150.1	P10635-1
	CYP2D6	ENST00000359033.4	TSL:1	c.513+122A>C		intron	N/A	ENSP00000351927.4	P10635-2
	CYP2D6	ENST00000360124.10	TSL:1	n.513+122A>C		intron	N/A	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 253 AN: 150238 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00583

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000927

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: 0.00

Gnomad OTH AF: 0.00146

GnomAD4 exome AF: 0.000192 AC: 195 AN: 1014756 Hom.: 9 AF XY: 0.000167 AC XY: 86 AN XY: 514526

African (AFR) AF: 0.00543 AC: 132 AN: 24292

American (AMR) AF: 0.00109 AC: 38 AN: 34948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23112

East Asian (EAS) AF: 0.00 AC: 0 AN: 34560

South Asian (SAS) AF: 0.0000140 AC: 1 AN: 71268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3570

European-Non Finnish (NFE) AF: 0.00000680 AC: 5 AN: 735182

Other (OTH) AF: 0.000416 AC: 19 AN: 45718

GnomAD4 genome AF: 0.00174 AC: 261 AN: 150350 Hom.: 7 Cov.: 31 AF XY: 0.00184 AC XY: 135 AN XY: 73420

African (AFR) AF: 0.00601 AC: 244 AN: 40584

American (AMR) AF: 0.000925 AC: 14 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67552

Other (OTH) AF: 0.00144 AC: 3 AN: 2080

Alfa AF: 0.000608 Hom.: 0

Bravo AF: 0.00202

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.7
DANN	Benign	0.32
PhyloP100		0.62
Mutation Taster		=100/0	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: rs267608290; hg19: chr22-42524664;