chr22-42141261-C-T

Variant names:

• chr22-42141261-C-T
• rs2743458
• ENST00000433992.2:c.1122G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The ENST00000433992.2(CYP2D7):​c.1122G>A​(p.Leu374Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 145,170 control chromosomes in the GnomAD database, including 39,928 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.73 (39928 hom., cov: 26)
  • Exomes 𝑓: 0.63 (240515 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP2D7 ENST00000433992.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.153
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008505195).
• BP7: Synonymous conserved (PhyloP=-0.153 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

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.1084G>A		non_coding_transcript_exon	Exon 7 of 9
	CYP2D7	NR_145674.3		n.1141G>A		non_coding_transcript_exon	Exon 7 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D7	ENST00000433992.2	TSL:1	c.1122G>A	p.Leu374Leu	synonymous	Exon 7 of 9	ENSP00000439604.1
	CYP2D7	ENST00000358097.8	TSL:1	c.1065G>A	p.Leu355Leu	synonymous	Exon 7 of 9	ENSP00000445124.1
	CYP2D7	ENST00000435101.2	TSL:1	n.187G>A		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.728 AC: 105576 AN: 145054 Hom.: 39880 Cov.: 26

Gnomad AFR AF: 0.928

Gnomad AMI AF: 0.755

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.660

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.667

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.693

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.625 AC: 732248 AN: 1170994 Hom.: 240515 Cov.: 27 AF XY: 0.625 AC XY: 368641 AN XY: 590240

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

African (AFR) AF: 0.930 AC: 22659 AN: 24354

American (AMR) AF: 0.532 AC: 21439 AN: 40314

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 15290 AN: 23314

East Asian (EAS) AF: 0.641 AC: 21534 AN: 33576

South Asian (SAS) AF: 0.556 AC: 43162 AN: 77632

European-Finnish (FIN) AF: 0.651 AC: 32071 AN: 49252

Middle Eastern (MID) AF: 0.596 AC: 2902 AN: 4870

European-Non Finnish (NFE) AF: 0.624 AC: 541212 AN: 867852

Other (OTH) AF: 0.642 AC: 31979 AN: 49830

⚠️ 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 AF: 0.728 AC: 105666 AN: 145170 Hom.: 39928 Cov.: 26 AF XY: 0.722 AC XY: 51058 AN XY: 70674

African (AFR) AF: 0.928 AC: 35575 AN: 38328

American (AMR) AF: 0.612 AC: 9020 AN: 14728

Ashkenazi Jewish (ASJ) AF: 0.660 AC: 2224 AN: 3370

East Asian (EAS) AF: 0.691 AC: 2548 AN: 3690

South Asian (SAS) AF: 0.568 AC: 2566 AN: 4516

European-Finnish (FIN) AF: 0.667 AC: 6952 AN: 10418

Middle Eastern (MID) AF: 0.682 AC: 199 AN: 292

European-Non Finnish (NFE) AF: 0.665 AC: 44522 AN: 66918

Other (OTH) AF: 0.687 AC: 1382 AN: 2012

Alfa AF: 0.615 Hom.: 2994

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
CADD	Benign	0.33
DEOGEN2	Benign	0.0038	T
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0085	T
PhyloP100		-0.15
Vest4		0.14

Splicing

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

Other links and lift over

dbSNP: rs2743458;