rs4987138

Positions:

• chr22-42143491-T-G

Variant summary

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

The ENST00000433992.2(CYP2D7):​c.272A>C​(p.Asp91Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00545 in 1,553,382 control chromosomes in the GnomAD database, including 260 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 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 0.023 (126 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (134 hom.)
• Consequence: CYP2D7 ENST00000433992.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.38

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]

CYP2D7 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020928085).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D7	NR_002570.6	n.291A>C		non_coding_transcript_exon_variant	2/9
CYP2D7	NR_145674.3	n.291A>C		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D7	ENST00000433992.2	c.272A>C	p.Asp91Ala	missense_variant	2/9	1		ENSP00000439604.1

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3515 AN: 151340 Hom.: 125 Cov.: 31

Gnomad AFR AF: 0.0781

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00928

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00694

Gnomad SAS AF: 0.00368

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000958

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00511 AC: 914 AN: 178830 Hom.: 18 AF XY: 0.00422 AC XY: 418 AN XY: 99000

Gnomad AFR exome AF: 0.0675

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.000338

Gnomad EAS exome AF: 0.00373

Gnomad SAS exome AF: 0.00304

Gnomad FIN exome AF: 0.0000913

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00352 AC: 4941 AN: 1401920 Hom.: 134 Cov.: 34 AF XY: 0.00332 AC XY: 2310 AN XY: 695260

Gnomad4 AFR exome AF: 0.0795

Gnomad4 AMR exome AF: 0.00397

Gnomad4 ASJ exome AF: 0.0000407

Gnomad4 EAS exome AF: 0.0186

Gnomad4 SAS exome AF: 0.00321

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.000902

Gnomad4 OTH exome AF: 0.00563

GnomAD4 genome AF: 0.0233 AC: 3525 AN: 151462 Hom.: 126 Cov.: 31 AF XY: 0.0231 AC XY: 1714 AN XY: 74052

Gnomad4 AFR AF: 0.0781

Gnomad4 AMR AF: 0.00926

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00696

Gnomad4 SAS AF: 0.00411

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.000943

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0109 Hom.: 9

Bravo AF: 0.0264

ExAC AF: 0.00313 AC: 363

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.67
DEOGEN2	Benign	0.0028	.;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.0050	N
LIST_S2	Benign	0.51	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.0	T
Vest4		0.23
MVP		0.030
ClinPred		0.038	T
GERP RS		1.4
Varity_R		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs4987138; hg19: chr22-42539492; COSMIC: COSV63852457; COSMIC: COSV63852457;