22-42126963-C-T

Position:

• chr22-42126963-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_000106.6(CYP2D6):​c.1203G>A​(p.Ser401=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00649 in 1,608,620 control chromosomes in the GnomAD database, including 341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (21 hom., cov: 31)
  • Exomes 𝑓: 0.0066 (320 hom.)
• Consequence: CYP2D6 NM_000106.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -13.6

Genes affected

CYP2D6 (HGNC:2625): (cytochrome P450 family 2 subfamily D member 6) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and is known to metabolize as many as 25% of commonly prescribed drugs. Its substrates include antidepressants, antipsychotics, analgesics and antitussives, beta adrenergic blocking agents, antiarrythmics and antiemetics. The gene is highly polymorphic in the human population; certain alleles result in the poor metabolizer phenotype, characterized by a decreased ability to metabolize the enzyme's substrates. Some individuals with the poor metabolizer phenotype have no functional protein since they carry 2 null alleles whereas in other individuals the gene is absent. This gene can vary in copy number and individuals with the ultrarapid metabolizer phenotype can have 3 or more active copies of the gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

NDUFA6-DT (HGNC:45273): (NDUFA6 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 22-42126963-C-T is Benign according to our data. Variant chr22-42126963-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2653237.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-42126963-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-13.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00662 (9647/1457382) while in subpopulation MID AF= 0.0287 (165/5740). AF 95% confidence interval is 0.0252. There are 320 homozygotes in gnomad4_exome. There are 4734 alleles in male gnomad4_exome subpopulation. Median coverage is 38. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 800 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D6	NM_000106.6	c.1203G>A	p.Ser401=	synonymous_variant	8/9	ENST00000645361.2
CYP2D6	NM_001025161.3	c.1050G>A	p.Ser350=	synonymous_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2	c.1203G>A	p.Ser401=	synonymous_variant	8/9		NM_000106.6	P1
NDUFA6-DT	ENST00000439129.5	n.1718+1556C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00531 AC: 803 AN: 151124 Hom.: 21 Cov.: 31

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00209

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00720

Gnomad OTH AF: 0.0126

GnomAD3 exomes AF: 0.00446 AC: 1021 AN: 228710 Hom.: 23 AF XY: 0.00451 AC XY: 557 AN XY: 123458

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00722

Gnomad ASJ exome AF: 0.00839

Gnomad EAS exome AF: 0.000117

Gnomad SAS exome AF: 0.00244

Gnomad FIN exome AF: 0.000489

Gnomad NFE exome AF: 0.00557

Gnomad OTH exome AF: 0.00875

GnomAD4 exome AF: 0.00662 AC: 9647 AN: 1457382 Hom.: 320 Cov.: 38 AF XY: 0.00653 AC XY: 4734 AN XY: 724750

Gnomad4 AFR exome AF: 0.000962

Gnomad4 AMR exome AF: 0.00892

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00297

Gnomad4 FIN exome AF: 0.000563

Gnomad4 NFE exome AF: 0.00724

Gnomad4 OTH exome AF: 0.00788

GnomAD4 genome AF: 0.00529 AC: 800 AN: 151238 Hom.: 21 Cov.: 31 AF XY: 0.00498 AC XY: 368 AN XY: 73900

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00961

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00209

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00719

Gnomad4 OTH AF: 0.0124

Alfa AF: 0.00693 Hom.: 5

Bravo AF: 0.00617

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

CYP2D6: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.96
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs28371732; hg19: chr22-42522965;