rs4633

chr22-19962712-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000754.4(COMT):c.186C>T(p.His62=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 1,613,292 control chromosomes in the GnomAD database, including 198,896 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15737 hom., cov: 34)
  • Exomes 𝑓: 0.50 (183159 hom.)
• Consequence: COMT NM_000754.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -1.83

Genes affected

COMT (HGNC:2228): (catechol-O-methyltransferase) Catechol-O-methyltransferase catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine. This O-methylation results in one of the major degradative pathways of the catecholamine transmitters. In addition to its role in the metabolism of endogenous substances, COMT is important in the metabolism of catechol drugs used in the treatment of hypertension, asthma, and Parkinson disease. COMT is found in two forms in tissues, a soluble form (S-COMT) and a membrane-bound form (MB-COMT). The differences between S-COMT and MB-COMT reside within the N-termini. Several transcript variants are formed through the use of alternative translation initiation sites and promoters. [provided by RefSeq, Sep 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 22-19962712-C-T is Benign according to our data. Variant chr22-19962712-C-T is described in ClinVar as [Benign]. Clinvar id is 256785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19962712-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.83 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMT	NM_000754.4	c.186C>T	p.His62=	synonymous_variant	3/6	ENST00000361682.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMT	ENST00000361682.11	c.186C>T	p.His62=	synonymous_variant	3/6	1	NM_000754.4	P2

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67786 AN: 152012 Hom.: 15738 Cov.: 34

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.425

GnomAD3 exomes AF: 0.463 AC: 115901 AN: 250082 Hom.: 27712 AF XY: 0.467 AC XY: 63276 AN XY: 135450

Gnomad AFR exome AF: 0.332

Gnomad AMR exome AF: 0.405

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.269

Gnomad SAS exome AF: 0.449

Gnomad FIN exome AF: 0.545

Gnomad NFE exome AF: 0.519

Gnomad OTH exome AF: 0.475

GnomAD4 exome AF: 0.497 AC: 726681 AN: 1461162 Hom.: 183159 Cov.: 71 AF XY: 0.497 AC XY: 361149 AN XY: 726878

Gnomad4 AFR exome AF: 0.328

Gnomad4 AMR exome AF: 0.409

Gnomad4 ASJ exome AF: 0.470

Gnomad4 EAS exome AF: 0.279

Gnomad4 SAS exome AF: 0.457

Gnomad4 FIN exome AF: 0.546

Gnomad4 NFE exome AF: 0.517

Gnomad4 OTH exome AF: 0.468

GnomAD4 genome AF: 0.446 AC: 67797 AN: 152130 Hom.: 15737 Cov.: 34 AF XY: 0.445 AC XY: 33124 AN XY: 74354

Gnomad4 AFR AF: 0.330

Gnomad4 AMR AF: 0.405

Gnomad4 ASJ AF: 0.460

Gnomad4 EAS AF: 0.270

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.551

Gnomad4 NFE AF: 0.518

Gnomad4 OTH AF: 0.423

Alfa AF: 0.489 Hom.: 22635

Bravo AF: 0.427

Asia WGS AF: 0.347 AC: 1206 AN: 3478

EpiCase AF: 0.499

EpiControl AF: 0.504

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

This variant is associated with the following publications: (PMID: 21486747) -

Tramadol response Other:1

drug response, no assertion criteria provided

research

Bruce Budowle Laboratory, University of North Texas Health Science Center

Apr 28, 2018

- T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.72
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4633; hg19: chr22-19950235; COSMIC: COSV52889434; COSMIC: COSV52889434;