22-42141394-C-G

Position:

• chr22-42141394-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000433992.2(CYP2D7):​c.989G>C​(p.Arg330Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,556,366 control chromosomes in the GnomAD database, including 39,808 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3398 hom., cov: 32)
  • Exomes 𝑓: 0.22 (36410 hom.)
• Consequence: CYP2D7 ENST00000433992.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.637

Genes affected

CYP2D7 (HGNC:2624): (cytochrome P450 family 2 subfamily D member 7 (gene/pseudogene)) This gene is a member of the cytochrome P450 gene superfamily. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This gene is a segregating pseudogene, where some individuals may have an allele that encodes a functional enzyme, while other individuals have an allele encoding a protein that is predicted to be non-functional. In this case, the functional allele is thought to be rare. This locus is part of a cluster of cytochrome P450 genes on chromosome 22. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001997888).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D7	NR_002570.6	n.1006-55G>C		intron_variant, non_coding_transcript_variant
CYP2D7	NR_145674.3	n.1008G>C		splice_region_variant, non_coding_transcript_exon_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D7	ENST00000433992.2	c.989G>C	p.Arg330Thr	missense_variant, splice_region_variant	7/9	1		P5

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29760 AN: 151914 Hom.: 3393 Cov.: 32

Gnomad AFR AF: 0.0947

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.222 AC: 311298 AN: 1404332 Hom.: 36410 Cov.: 25 AF XY: 0.223 AC XY: 156392 AN XY: 700160

Gnomad4 AFR exome AF: 0.0931

Gnomad4 AMR exome AF: 0.213

Gnomad4 ASJ exome AF: 0.175

Gnomad4 EAS exome AF: 0.133

Gnomad4 SAS exome AF: 0.239

Gnomad4 FIN exome AF: 0.339

Gnomad4 NFE exome AF: 0.224

Gnomad4 OTH exome AF: 0.215

GnomAD4 genome AF: 0.196 AC: 29769 AN: 152034 Hom.: 3398 Cov.: 32 AF XY: 0.203 AC XY: 15098 AN XY: 74318

Gnomad4 AFR AF: 0.0946

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.249

Gnomad4 FIN AF: 0.349

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.218

Alfa AF: 0.141 Hom.: 406

Bravo AF: 0.180

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.5
DEOGEN2	Benign	0.0030	T
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0020	T
Vest4		0.23

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2854741; hg19: chr22-42537404;