22-42126682-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000106.6(CYP2D6):c.1386G>C(p.Gln462His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,602,978 control chromosomes in the GnomAD database, including 22 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00010 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00033 (21 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2D6	NM_000106.6	c.1386G>C	p.Gln462His	missense_variant	9/9	ENST00000645361.2
CYP2D6	NM_001025161.3	c.1233G>C	p.Gln411His	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2D6	ENST00000645361.2	c.1386G>C	p.Gln462His	missense_variant	9/9		NM_000106.6	P1
NDUFA6-DT	ENST00000439129.5	n.1718+1275C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000996 AC: 15 AN: 150552 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000493

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000120 AC: 28 AN: 233624 Hom.: 1 AF XY: 0.000119 AC XY: 15 AN XY: 126374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000330 AC: 479 AN: 1452312 Hom.: 21 Cov.: 38 AF XY: 0.000337 AC XY: 243 AN XY: 721704

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000424

Gnomad4 OTH exome AF: 0.000167

GnomAD4 genome AF: 0.0000996 AC: 15 AN: 150666 Hom.: 1 Cov.: 31 AF XY: 0.0000815 AC XY: 6 AN XY: 73626

Gnomad4 AFR AF: 0.0000492

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000192

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000173 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.0000992 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

The c.1386G>C (p.Q462H) alteration is located in exon 9 (coding exon 9) of the CYP2D6 gene. This alteration results from a G to C substitution at nucleotide position 1386, causing the glutamine (Q) at amino acid position 462 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.020	T;T;T;T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Uncertain	2.4	M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
Vest4		0.80, 0.79, 0.78
MutPred		0.92		Loss of stability (P = 0.1573);Loss of stability (P = 0.1573);Loss of stability (P = 0.1573);.;.;
MVP		0.84
MPC		0.47
ClinPred		0.42	T
GERP RS		3.8
Varity_R		0.54
gMVP		0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs138229048; hg19: chr22-42522684;