chr22-42129770-G-T

Position:

• chr22-42129770-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM5 BP4_Strong BS2

The NM_000106.6(CYP2D6):​c.320C>A​(p.Thr107Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,608,900 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T107I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00079 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (13 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.91

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 -6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-42129770-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.006817639).
• BS2: High AC in GnomAd4 at 120 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.320C>A	p.Thr107Asn	missense_variant	2/9	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.320C>A	p.Thr107Asn	missense_variant	2/8		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.320C>A	p.Thr107Asn	missense_variant	2/9		NM_000106.6	ENSP00000496150	P1
NDUFA6-DT	ENST00000439129.5	n.1718+4363G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000793 AC: 120 AN: 151272 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.0336

Gnomad AMR AF: 0.00507

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000164 AC: 40 AN: 244170 Hom.: 6 AF XY: 0.000142 AC XY: 19 AN XY: 133408

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000915

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000547

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000178 AC: 260 AN: 1457518 Hom.: 13 Cov.: 33 AF XY: 0.000165 AC XY: 120 AN XY: 725176

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00393

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000550

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000793 AC: 120 AN: 151382 Hom.: 3 Cov.: 32 AF XY: 0.000933 AC XY: 69 AN XY: 73972

Gnomad4 AFR AF: 0.0000244

Gnomad4 AMR AF: 0.00506

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000626

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000475

ExAC AF: 0.000827 AC: 100

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.0030
DANN	Benign	0.55
DEOGEN2	Benign	0.0011	T;T;T;T;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.12	.;.;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0068	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.025	N;N;N;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.26	.;.;N;.;N
REVEL	Benign	0.14
Sift	Benign	0.31	.;.;T;.;T
Sift4G	Benign	0.22	.;.;T;T;T
Vest4		0.12, 0.13, 0.12
MutPred		0.52		Gain of relative solvent accessibility (P = 0.0905);Gain of relative solvent accessibility (P = 0.0905);Gain of relative solvent accessibility (P = 0.0905);.;Gain of relative solvent accessibility (P = 0.0905);
MVP		0.52
MPC		0.13
ClinPred		0.040	T
GERP RS		-1.7
Varity_R		0.19
gMVP		0.72

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: rs28371706; hg19: chr22-42525772;