22-42141394-C-G

Variant names:

• chr22-42141394-C-G
• rs2854741
• ENST00000433992.2:c.989G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CYP2D7	NR_145674.3	n.1008G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 9
CYP2D7	NR_002570.6	n.1006-55G>C		intron_variant	Intron 6 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2D7	ENST00000433992.2	c.989G>C	p.Arg330Thr	missense_variant, splice_region_variant	Exon 7 of 9	1		ENSP00000439604.1

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

African (AFR) AF: 0.0931 AC: 3017 AN: 32402

American (AMR) AF: 0.213 AC: 9065 AN: 42616

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 4465 AN: 25552

East Asian (EAS) AF: 0.133 AC: 5200 AN: 39154

South Asian (SAS) AF: 0.239 AC: 20044 AN: 83942

European-Finnish (FIN) AF: 0.339 AC: 17746 AN: 52336

Middle Eastern (MID) AF: 0.220 AC: 1247 AN: 5662

European-Non Finnish (NFE) AF: 0.224 AC: 237941 AN: 1064174

Other (OTH) AF: 0.215 AC: 12573 AN: 58494

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

African (AFR) AF: 0.0946 AC: 3929 AN: 41542

American (AMR) AF: 0.227 AC: 3470 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 579 AN: 3468

East Asian (EAS) AF: 0.119 AC: 612 AN: 5164

South Asian (SAS) AF: 0.249 AC: 1199 AN: 4814

European-Finnish (FIN) AF: 0.349 AC: 3689 AN: 10572

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15615 AN: 67864

Other (OTH) AF: 0.218 AC: 461 AN: 2110

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
PhyloP100		-0.64
Vest4		0.23

Splicing

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

Other links and lift over

dbSNP: rs2854741; hg19: chr22-42537404;