chr22-42129193-T-C

Variant names:

• chr22-42129193-T-C
• rs267608305
• NM_000106.6:c.353-8A>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.353-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,435,886 control chromosomes in the GnomAD database, including 2 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. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000066 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP2D6 NM_000106.6 splice_region, intron
• Scores: Splicing: ADA: 0.000008301
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.788
• Publications: 0 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 (BayesDel_noAF=-1.03).

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.353-8A>G		splice_region intron	N/A	NP_000097.3
	CYP2D6	NM_001025161.3		c.353-249A>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.353-8A>G		splice_region intron	N/A	ENSP00000496150.1	P10635-1
	CYP2D6	ENST00000359033.4	TSL:1	c.353-249A>G		intron	N/A	ENSP00000351927.4	P10635-2
	CYP2D6	ENST00000360124.10	TSL:1	n.353-249A>G		intron	N/A	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes AF: 0.0000663 AC: 10 AN: 150904 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.0000444

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000337 AC: 8 AN: 237668 AF XY: 0.0000384

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000567

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000199 AC: 286 AN: 1435886 Hom.: 2 Cov.: 37 AF XY: 0.000225 AC XY: 161 AN XY: 714444

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

African (AFR) AF: 0.000120 AC: 4 AN: 33248

American (AMR) AF: 0.000226 AC: 10 AN: 44206

Ashkenazi Jewish (ASJ) AF: 0.000271 AC: 7 AN: 25864

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39540

South Asian (SAS) AF: 0.000128 AC: 11 AN: 85736

European-Finnish (FIN) AF: 0.000335 AC: 15 AN: 44748

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.000203 AC: 223 AN: 1097096

Other (OTH) AF: 0.000151 AC: 9 AN: 59700

⚠️ 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: 0.0000662 AC: 10 AN: 151012 Hom.: 1 Cov.: 33 AF XY: 0.0000542 AC XY: 4 AN XY: 73824

African (AFR) AF: 0.000122 AC: 5 AN: 41022

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00352 AC: 1 AN: 284

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67552

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000349 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.56
DANN	Benign	0.42
PhyloP100		-0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000083
dbscSNV1_RF	Benign	0.038
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs267608305; hg19: chr22-42525195;