22-42130547-T-C

Variant names:

• chr22-42130547-T-C
• rs1081000
• NM_000106.6:c.180+65A>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+65A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.083 (928 hom., cov: 23)
  • Exomes 𝑓: 0.13 (24548 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP2D6 NM_000106.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50
• Publications: 8 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=1.554).

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+65A>G		intron	N/A	NP_000097.3
	CYP2D6	NM_001025161.3		c.180+65A>G		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+65A>G		intron	N/A	ENSP00000496150.1	P10635-1
	CYP2D6	ENST00000359033.4	TSL:1	c.180+65A>G		intron	N/A	ENSP00000351927.4	P10635-2
	CYP2D6	ENST00000360124.10	TSL:1	n.180+65A>G		intron	N/A	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes AF: 0.0834 AC: 8119 AN: 97292 Hom.: 925 Cov.: 23

Gnomad AFR AF: 0.0789

Gnomad AMI AF: 0.0432

Gnomad AMR AF: 0.0849

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0201

Gnomad SAS AF: 0.0938

Gnomad FIN AF: 0.0904

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.0866

Gnomad OTH AF: 0.108

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.128 AC: 111101 AN: 871158 Hom.: 24548 Cov.: 20 AF XY: 0.132 AC XY: 57248 AN XY: 433644

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

African (AFR) AF: 0.151 AC: 2981 AN: 19716

American (AMR) AF: 0.137 AC: 3599 AN: 26208

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 3964 AN: 16072

East Asian (EAS) AF: 0.0344 AC: 1090 AN: 31714

South Asian (SAS) AF: 0.239 AC: 11975 AN: 50190

European-Finnish (FIN) AF: 0.178 AC: 5663 AN: 31842

Middle Eastern (MID) AF: 0.186 AC: 555 AN: 2988

European-Non Finnish (NFE) AF: 0.116 AC: 75865 AN: 655894

Other (OTH) AF: 0.148 AC: 5409 AN: 36534

⚠️ 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: 0.0835 AC: 8127 AN: 97364 Hom.: 928 Cov.: 23 AF XY: 0.0825 AC XY: 3892 AN XY: 47156

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

African (AFR) AF: 0.0790 AC: 2056 AN: 26020

American (AMR) AF: 0.0853 AC: 856 AN: 10034

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 320 AN: 2168

East Asian (EAS) AF: 0.0199 AC: 86 AN: 4320

South Asian (SAS) AF: 0.0935 AC: 261 AN: 2790

European-Finnish (FIN) AF: 0.0904 AC: 547 AN: 6050

Middle Eastern (MID) AF: 0.250 AC: 34 AN: 136

European-Non Finnish (NFE) AF: 0.0866 AC: 3795 AN: 43842

Other (OTH) AF: 0.107 AC: 143 AN: 1332

⚠️ 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: 0.293 Hom.: 1041

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
CADD	Benign	1.6
PhyloP100		-1.5
PromoterAI		0.016	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1081000;