rs16947

Variant names:

• chr22-42127941-G-A
• rs16947
• NM_000106.6:c.886C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-42127941-G-A
• chr22-42127941-G-C
• chr22-42127941-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000106.6(CYP2D6):​c.886C>T​(p.Arg296Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 1,610,098 control chromosomes in the GnomAD database, including 108,422 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R296H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.39 (13067 hom., cov: 32)
  • Exomes 𝑓: 0.34 (95355 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.921
• Publications: 383 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008255243).
• BP6: Variant 22-42127941-G-A is Benign according to our data. Variant chr22-42127941-G-A is described in ClinVar as Benign. ClinVar VariationId is 242771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000106.6. 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
	CYP2D6	NM_000106.6	MANE Select	c.886C>T	p.Arg296Cys	missense	Exon 6 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.733C>T	p.Arg245Cys	missense	Exon 5 of 8	NP_001020332.2	P10635-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	ENST00000645361.2	MANE Select	c.886C>T	p.Arg296Cys	missense	Exon 6 of 9	ENSP00000496150.1	P10635-1
	CYP2D6	ENST00000359033.4	TSL:1	c.733C>T	p.Arg245Cys	missense	Exon 5 of 8	ENSP00000351927.4	P10635-2
	CYP2D6	ENST00000360124.10	TSL:1	n.691-7C>T		splice_region intron	N/A	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58085 AN: 150702 Hom.: 13023 Cov.: 32

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.382

GnomAD4 exome AF: 0.336 AC: 490905 AN: 1459282 Hom.: 95355 Cov.: 56 AF XY: 0.339 AC XY: 245894 AN XY: 725958

African (AFR) AF: 0.527 AC: 17534 AN: 33292

American (AMR) AF: 0.285 AC: 12714 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 10603 AN: 26114

East Asian (EAS) AF: 0.144 AC: 5703 AN: 39588

South Asian (SAS) AF: 0.384 AC: 33071 AN: 86116

European-Finnish (FIN) AF: 0.387 AC: 20656 AN: 53394

Middle Eastern (MID) AF: 0.425 AC: 2448 AN: 5754

European-Non Finnish (NFE) AF: 0.330 AC: 366827 AN: 1110108

Other (OTH) AF: 0.354 AC: 21349 AN: 60246

GnomAD4 genome AF: 0.386 AC: 58174 AN: 150816 Hom.: 13067 Cov.: 32 AF XY: 0.386 AC XY: 28466 AN XY: 73670

African (AFR) AF: 0.518 AC: 21104 AN: 40762

American (AMR) AF: 0.344 AC: 5230 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1366 AN: 3468

East Asian (EAS) AF: 0.148 AC: 757 AN: 5114

South Asian (SAS) AF: 0.382 AC: 1822 AN: 4774

European-Finnish (FIN) AF: 0.389 AC: 4104 AN: 10540

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.335 AC: 22641 AN: 67648

Other (OTH) AF: 0.378 AC: 792 AN: 2094

Alfa AF: 0.322 Hom.: 2728

Bravo AF: 0.386

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_noAF	Benign	-0.92
CADD	Benign	15
DEOGEN2	Benign	0.017	T
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0083	T
PhyloP100		-0.92
Sift4G	Benign	0.18	T
Vest4		0.17
gMVP		0.61

Splicing

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

Other links and lift over

dbSNP: rs16947; hg19: chr22-42523943;