22-42130565-A-G

Variant names:

• chr22-42130565-A-G
• rs1080998
• NM_000106.6:c.180+47T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000106.6(CYP2D6):​c.180+47T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0678 in 950,202 control chromosomes in the GnomAD database, including 22,095 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.046 (331 hom., cov: 23)
  • Exomes 𝑓: 0.068 (22095 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP2D6 NM_000106.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.893
• Publications: 5 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (Cadd=0.724).

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.180+47T>C		intron	N/A	NP_000097.3
	CYP2D6	NM_001025161.3		c.180+47T>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.180+47T>C		intron	N/A	ENSP00000496150.1	P10635-1
	CYP2D6	ENST00000359033.4	TSL:1	c.180+47T>C		intron	N/A	ENSP00000351927.4	P10635-2
	CYP2D6	ENST00000360124.10	TSL:1	n.180+47T>C		intron	N/A	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes AF: 0.0462 AC: 4299 AN: 93046 Hom.: 329 Cov.: 23

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.0337

Gnomad AMR AF: 0.0491

Gnomad ASJ AF: 0.0837

Gnomad EAS AF: 0.0115

Gnomad SAS AF: 0.0473

Gnomad FIN AF: 0.0532

Gnomad MID AF: 0.135

Gnomad NFE AF: 0.0446

Gnomad OTH AF: 0.0578

GnomAD4 exome AF: 0.0678 AC: 64445 AN: 950202 Hom.: 22095 Cov.: 26 AF XY: 0.0726 AC XY: 34297 AN XY: 472634

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0873 AC: 1857 AN: 21266

American (AMR) AF: 0.0821 AC: 2459 AN: 29952

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 2990 AN: 17060

East Asian (EAS) AF: 0.0369 AC: 1203 AN: 32608

South Asian (SAS) AF: 0.154 AC: 8030 AN: 52284

European-Finnish (FIN) AF: 0.161 AC: 5346 AN: 33222

Middle Eastern (MID) AF: 0.130 AC: 429 AN: 3310

European-Non Finnish (NFE) AF: 0.0528 AC: 38121 AN: 721394

Other (OTH) AF: 0.103 AC: 4010 AN: 39106

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0462 AC: 4300 AN: 93098 Hom.: 331 Cov.: 23 AF XY: 0.0453 AC XY: 2043 AN XY: 45100

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0483 AC: 1203 AN: 24930

American (AMR) AF: 0.0492 AC: 464 AN: 9434

Ashkenazi Jewish (ASJ) AF: 0.0837 AC: 167 AN: 1996

East Asian (EAS) AF: 0.0113 AC: 49 AN: 4328

South Asian (SAS) AF: 0.0482 AC: 125 AN: 2592

European-Finnish (FIN) AF: 0.0532 AC: 305 AN: 5730

Middle Eastern (MID) AF: 0.142 AC: 19 AN: 134

European-Non Finnish (NFE) AF: 0.0446 AC: 1873 AN: 42022

Other (OTH) AF: 0.0576 AC: 72 AN: 1250

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.155 Hom.: 651

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
CADD	Benign	0.72
PhyloP100		-0.89

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1080998;