22-42130578-C-G

Variant names:

• chr22-42130578-C-G
• rs1080995
• NM_000106.6:c.180+34G>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+34G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 969,088 control chromosomes in the GnomAD database, including 28,570 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), 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 0.066 (754 hom., cov: 23)
  • Exomes 𝑓: 0.11 (27816 hom.)
• Consequence: CYP2D6 NM_000106.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• Publications: 16 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=0.121).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	NM_000106.6	MANE Select	c.180+34G>C		intron	N/A	NP_000097.3
	CYP2D6	NM_001025161.3		c.180+34G>C		intron	N/A	NP_001020332.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	ENST00000645361.2	MANE Select	c.180+34G>C		intron	N/A	ENSP00000496150.1
	CYP2D6	ENST00000359033.4	TSL:1	c.180+34G>C		intron	N/A	ENSP00000351927.4
	CYP2D6	ENST00000360124.10	TSL:1	n.180+34G>C		intron	N/A	ENSP00000353241.6

Frequencies

GnomAD3 genomes AF: 0.0655 AC: 6056 AN: 92438 Hom.: 751 Cov.: 23

Gnomad AFR AF: 0.0653

Gnomad AMI AF: 0.0369

Gnomad AMR AF: 0.0684

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.0171

Gnomad SAS AF: 0.0658

Gnomad FIN AF: 0.0743

Gnomad MID AF: 0.200

Gnomad NFE AF: 0.0657

Gnomad OTH AF: 0.0736

GnomAD4 exome AF: 0.113 AC: 98999 AN: 876594 Hom.: 27816 Cov.: 29 AF XY: 0.121 AC XY: 52718 AN XY: 436838

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

African (AFR) AF: 0.137 AC: 2732 AN: 19914

American (AMR) AF: 0.134 AC: 3843 AN: 28756

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 4033 AN: 16070

East Asian (EAS) AF: 0.0544 AC: 1790 AN: 32902

South Asian (SAS) AF: 0.233 AC: 12079 AN: 51916

European-Finnish (FIN) AF: 0.259 AC: 8876 AN: 34292

Middle Eastern (MID) AF: 0.193 AC: 594 AN: 3084

European-Non Finnish (NFE) AF: 0.0910 AC: 59334 AN: 652280

Other (OTH) AF: 0.153 AC: 5718 AN: 37380

⚠️ 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 AF: 0.0655 AC: 6060 AN: 92494 Hom.: 754 Cov.: 23 AF XY: 0.0642 AC XY: 2871 AN XY: 44746

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

African (AFR) AF: 0.0653 AC: 1629 AN: 24934

American (AMR) AF: 0.0687 AC: 653 AN: 9512

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 246 AN: 1970

East Asian (EAS) AF: 0.0169 AC: 73 AN: 4320

South Asian (SAS) AF: 0.0667 AC: 174 AN: 2610

European-Finnish (FIN) AF: 0.0743 AC: 418 AN: 5628

Middle Eastern (MID) AF: 0.206 AC: 26 AN: 126

European-Non Finnish (NFE) AF: 0.0657 AC: 2728 AN: 41530

Other (OTH) AF: 0.0733 AC: 89 AN: 1214

⚠️ 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: 0.314 Hom.: 1672

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
CADD	Benign	0.12
PhyloP100		-1.5
PromoterAI		-0.0054	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1080995;