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GeneBe

rs4633

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -1.83
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
COMTNM_000754.4 linkuse as main transcriptc.186C>T p.His62= synonymous_variant 3/6 ENST00000361682.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COMTENST00000361682.11 linkuse as main transcriptc.186C>T p.His62= synonymous_variant 3/61 NM_000754.4 P2P21964-1

Frequencies

GnomAD3 genomes
AF:
0.446
AC:
67786
AN:
152012
Hom.:
15738
Cov.:
34
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMay 04, 2021This variant is associated with the following publications: (PMID: 21486747) -
Tramadol response Other:1
drug response, no assertion criteria providedresearchBruce Budowle Laboratory, University of North Texas Health Science CenterApr 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4633; hg19: chr22-19950235; COSMIC: COSV52889434; COSMIC: COSV52889434; API