chr22-42143491-T-G

Variant names:

• chr22-42143491-T-G
• rs4987138
• ENST00000433992.2:c.272A>C

Variant summary

Our verdict is Benign. The variant received -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. 10/13 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
• 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 -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.

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.291A>C		non_coding_transcript_exon	Exon 2 of 9
	CYP2D7	NR_145674.3		n.291A>C		non_coding_transcript_exon	Exon 2 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D7	ENST00000433992.2	TSL:1	c.272A>C	p.Asp91Ala	missense	Exon 2 of 9	ENSP00000439604.1
	CYP2D7	ENST00000358097.8	TSL:1	c.272A>C	p.Asp91Ala	missense	Exon 2 of 9	ENSP00000445124.1
	CYP2D7	ENST00000610593.4	TSL:1	n.357A>C		non_coding_transcript_exon	Exon 2 of 6

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

GnomAD2 exomes AF: 0.00511 AC: 914 AN: 178830 AF XY: 0.00422

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 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

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

African (AFR) AF: 0.0795 AC: 2520 AN: 31686

American (AMR) AF: 0.00397 AC: 151 AN: 38018

Ashkenazi Jewish (ASJ) AF: 0.0000407 AC: 1 AN: 24596

East Asian (EAS) AF: 0.0186 AC: 666 AN: 35768

South Asian (SAS) AF: 0.00321 AC: 262 AN: 81598

European-Finnish (FIN) AF: 0.000262 AC: 11 AN: 41954

Middle Eastern (MID) AF: 0.00536 AC: 27 AN: 5040

European-Non Finnish (NFE) AF: 0.000902 AC: 979 AN: 1085742

Other (OTH) AF: 0.00563 AC: 324 AN: 57518

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

African (AFR) AF: 0.0781 AC: 3229 AN: 41360

American (AMR) AF: 0.00926 AC: 141 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00696 AC: 35 AN: 5032

South Asian (SAS) AF: 0.00411 AC: 19 AN: 4622

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10576

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000943 AC: 64 AN: 67864

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

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 v4.9

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
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.4
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

Other links and lift over

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