22-42130569-G-C

Variant names:

• chr22-42130569-G-C
• rs1080997
• NM_000106.6:c.180+43C>G

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+43C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0725 in 954,444 control chromosomes in the GnomAD database, including 23,313 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 0.044 (314 hom., cov: 23)
  • Exomes 𝑓: 0.072 (23313 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP2D6 NM_000106.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00100
• Publications: 7 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=1.032).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.180+43C>G		intron_variant	Intron 1 of 8	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.180+43C>G		intron_variant	Intron 1 of 7		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.180+43C>G		intron_variant	Intron 1 of 8		NM_000106.6	ENSP00000496150.1

Frequencies

GnomAD3 genomes AF: 0.0439 AC: 4038 AN: 91918 Hom.: 310 Cov.: 23

Gnomad AFR AF: 0.0470

Gnomad AMI AF: 0.0302

Gnomad AMR AF: 0.0491

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.0101

Gnomad SAS AF: 0.0399

Gnomad FIN AF: 0.0524

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0413

Gnomad OTH AF: 0.0547

GnomAD4 exome AF: 0.0725 AC: 69167 AN: 954444 Hom.: 23313 Cov.: 27 AF XY: 0.0772 AC XY: 36688 AN XY: 474980

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

African (AFR) AF: 0.0942 AC: 2012 AN: 21370

American (AMR) AF: 0.0877 AC: 2678 AN: 30526

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 3198 AN: 17208

East Asian (EAS) AF: 0.0397 AC: 1301 AN: 32734

South Asian (SAS) AF: 0.157 AC: 8295 AN: 52938

European-Finnish (FIN) AF: 0.182 AC: 6077 AN: 33420

Middle Eastern (MID) AF: 0.135 AC: 444 AN: 3280

European-Non Finnish (NFE) AF: 0.0564 AC: 40818 AN: 723320

Other (OTH) AF: 0.110 AC: 4344 AN: 39648

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0439 AC: 4040 AN: 91968 Hom.: 314 Cov.: 23 AF XY: 0.0430 AC XY: 1918 AN XY: 44602

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

African (AFR) AF: 0.0470 AC: 1158 AN: 24650

American (AMR) AF: 0.0493 AC: 468 AN: 9486

Ashkenazi Jewish (ASJ) AF: 0.0836 AC: 163 AN: 1950

East Asian (EAS) AF: 0.00989 AC: 43 AN: 4346

South Asian (SAS) AF: 0.0416 AC: 105 AN: 2526

European-Finnish (FIN) AF: 0.0524 AC: 296 AN: 5648

Middle Eastern (MID) AF: 0.119 AC: 14 AN: 118

European-Non Finnish (NFE) AF: 0.0413 AC: 1707 AN: 41374

Other (OTH) AF: 0.0546 AC: 66 AN: 1208

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.193 Hom.: 980

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CADD	Benign	1.0
PhyloP100		0.0010
PromoterAI		0.0034	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1080997; hg19: -;