22-42130571-G-T

Variant names:

• chr22-42130571-G-T
• rs1080996
• NM_000106.6:c.180+41C>A

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+41C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0795 in 924,438 control chromosomes in the GnomAD database, including 24,431 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 0.047 (378 hom., cov: 23)
  • Exomes 𝑓: 0.080 (24431 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP2D6 NM_000106.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.66
• Publications: 10 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=0.132).

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+41C>A		intron	N/A	NP_000097.3
	CYP2D6	NM_001025161.3		c.180+41C>A		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+41C>A		intron	N/A	ENSP00000496150.1	P10635-1
	CYP2D6	ENST00000359033.4	TSL:1	c.180+41C>A		intron	N/A	ENSP00000351927.4	P10635-2
	CYP2D6	ENST00000360124.10	TSL:1	n.180+41C>A		intron	N/A	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes AF: 0.0473 AC: 4338 AN: 91778 Hom.: 372 Cov.: 23

Gnomad AFR AF: 0.0492

Gnomad AMI AF: 0.0347

Gnomad AMR AF: 0.0526

Gnomad ASJ AF: 0.0937

Gnomad EAS AF: 0.0115

Gnomad SAS AF: 0.0471

Gnomad FIN AF: 0.0571

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0543

GnomAD4 exome AF: 0.0795 AC: 73500 AN: 924438 Hom.: 24431 Cov.: 27 AF XY: 0.0845 AC XY: 38925 AN XY: 460716

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

African (AFR) AF: 0.100 AC: 2092 AN: 20890

American (AMR) AF: 0.0927 AC: 2853 AN: 30772

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 3353 AN: 17018

East Asian (EAS) AF: 0.0434 AC: 1425 AN: 32840

South Asian (SAS) AF: 0.164 AC: 8527 AN: 51992

European-Finnish (FIN) AF: 0.202 AC: 6780 AN: 33646

Middle Eastern (MID) AF: 0.148 AC: 479 AN: 3232

European-Non Finnish (NFE) AF: 0.0625 AC: 43435 AN: 695280

Other (OTH) AF: 0.118 AC: 4556 AN: 38768

⚠️ 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: 0.0473 AC: 4345 AN: 91836 Hom.: 378 Cov.: 23 AF XY: 0.0465 AC XY: 2070 AN XY: 44524

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

African (AFR) AF: 0.0494 AC: 1213 AN: 24574

American (AMR) AF: 0.0529 AC: 501 AN: 9474

Ashkenazi Jewish (ASJ) AF: 0.0937 AC: 180 AN: 1922

East Asian (EAS) AF: 0.0113 AC: 49 AN: 4350

South Asian (SAS) AF: 0.0484 AC: 124 AN: 2564

European-Finnish (FIN) AF: 0.0571 AC: 321 AN: 5626

Middle Eastern (MID) AF: 0.143 AC: 18 AN: 126

European-Non Finnish (NFE) AF: 0.0448 AC: 1851 AN: 41340

Other (OTH) AF: 0.0543 AC: 65 AN: 1198

⚠️ 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: 0.217 Hom.: 980

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
CADD	Benign	0.13
PhyloP100		-4.7
PromoterAI		0.0039	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1080996;