rs199515619

Variant names:

• chr22-42141910-T-G
• rs199515619
• ENST00000433992.2:c.802A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000433992.2(CYP2D7):​c.802A>C​(p.Thr268Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,610,476 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (31 hom.)
• Consequence: CYP2D7 ENST00000433992.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.13
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 22-42141910-T-G is Benign according to our data. Variant chr22-42141910-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2653243.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00225 (3276/1458314) while in subpopulation MID AF = 0.0202 (116/5754). AF 95% confidence interval is 0.0172. There are 31 homozygotes in GnomAdExome4. There are 1675 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000433992.2. 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
	CYP2D7	NR_002570.6		n.821A>C		non_coding_transcript_exon	Exon 5 of 9
	CYP2D7	NR_145674.3		n.821A>C		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D7	ENST00000433992.2	TSL:1	c.802A>C	p.Thr268Pro	missense	Exon 5 of 9	ENSP00000439604.1
	CYP2D7	ENST00000358097.8	TSL:1	c.802A>C	p.Thr268Pro	missense	Exon 5 of 9	ENSP00000445124.1
	CYP2D7	ENST00000435101.2	TSL:1	n.15A>C		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 552 AN: 152044 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00587

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.0306

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.00395

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00332 AC: 818 AN: 246470 AF XY: 0.00332

Gnomad AFR exome AF: 0.00466

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.0326

Gnomad EAS exome AF: 0.000386

Gnomad FIN exome AF: 0.000328

Gnomad NFE exome AF: 0.00168

Gnomad OTH exome AF: 0.00514

GnomAD4 exome AF: 0.00225 AC: 3276 AN: 1458314 Hom.: 31 Cov.: 34 AF XY: 0.00231 AC XY: 1675 AN XY: 725194

African (AFR) AF: 0.00706 AC: 236 AN: 33416

American (AMR) AF: 0.00275 AC: 122 AN: 44392

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 826 AN: 26034

East Asian (EAS) AF: 0.00680 AC: 269 AN: 39570

South Asian (SAS) AF: 0.00277 AC: 236 AN: 85194

European-Finnish (FIN) AF: 0.000395 AC: 21 AN: 53206

Middle Eastern (MID) AF: 0.0202 AC: 116 AN: 5754

European-Non Finnish (NFE) AF: 0.00106 AC: 1173 AN: 1110516

Other (OTH) AF: 0.00460 AC: 277 AN: 60232

GnomAD4 genome AF: 0.00361 AC: 550 AN: 152162 Hom.: 4 Cov.: 33 AF XY: 0.00370 AC XY: 275 AN XY: 74394

African (AFR) AF: 0.00587 AC: 244 AN: 41532

American (AMR) AF: 0.00386 AC: 59 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0306 AC: 106 AN: 3466

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5156

South Asian (SAS) AF: 0.00395 AC: 19 AN: 4810

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00132 AC: 90 AN: 67968

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00852 Hom.: 1

Bravo AF: 0.00393

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.75
DANN	Benign	0.73
PhyloP100		-1.1

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

Other links and lift over

dbSNP: rs199515619; hg19: chr22-42537920;