chr22-42129297-A-G

Variant names:

• chr22-42129297-A-G
• rs267608306
• NM_000106.6:c.353-112T>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.353-112T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000377 in 1,352,686 control chromosomes in the GnomAD database, including 1 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 0.00017 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CYP2D6 NM_000106.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.295
• 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=-0.9).
• BS2: High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.353-112T>C		intron_variant	Intron 2 of 8	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.353-353T>C		intron_variant	Intron 2 of 7		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.353-112T>C		intron_variant	Intron 2 of 8		NM_000106.6	ENSP00000496150.1

Frequencies

GnomAD3 genomes AF: 0.000165 AC: 25 AN: 151544 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000961

GnomAD4 exome AF: 0.0000208 AC: 25 AN: 1201028 Hom.: 0 Cov.: 19 AF XY: 0.0000233 AC XY: 14 AN XY: 601314

African (AFR) AF: 0.00 AC: 0 AN: 28042

American (AMR) AF: 0.00 AC: 0 AN: 36302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24306

East Asian (EAS) AF: 0.000246 AC: 9 AN: 36604

South Asian (SAS) AF: 0.00 AC: 0 AN: 76082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5412

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 907466

Other (OTH) AF: 0.000307 AC: 16 AN: 52108

GnomAD4 genome AF: 0.000171 AC: 26 AN: 151658 Hom.: 1 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74154

African (AFR) AF: 0.0000243 AC: 1 AN: 41180

American (AMR) AF: 0.00131 AC: 20 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67854

Other (OTH) AF: 0.00143 AC: 3 AN: 2104

Alfa AF: 0.0000534 Hom.: 0

Bravo AF: 0.0000982

Asia WGS AF: 0.000870 AC: 3 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.39
PhyloP100		-0.29

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: rs267608306; hg19: chr22-42525299;