rs769224

Variant names:

• chr22-19964281-G-A
• rs769224
• NM_000754.4:c.597G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000754.4(COMT):​c.597G>A​(p.Pro199Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 1,613,964 control chromosomes in the GnomAD database, including 799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (219 hom., cov: 33)
  • Exomes 𝑓: 0.025 (580 hom.)
• Consequence: COMT NM_000754.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -1.92
• Publications: 26 publications found

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]

COMT Gene-Disease associations (from GenCC):

• paroxysmal dyskinesia

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.121).
• BP6: Variant 22-19964281-G-A is Benign according to our data. Variant chr22-19964281-G-A is described in ClinVar as Benign. ClinVar VariationId is 828956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0909 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000754.4. 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
	COMT	NM_000754.4	MANE Select	c.597G>A	p.Pro199Pro	synonymous	Exon 5 of 6	NP_000745.1	P21964-1
	COMT	NM_001135161.2		c.597G>A	p.Pro199Pro	synonymous	Exon 5 of 6	NP_001128633.1	P21964-1
	COMT	NM_001135162.2		c.597G>A	p.Pro199Pro	synonymous	Exon 5 of 6	NP_001128634.1	P21964-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.597G>A	p.Pro199Pro	synonymous	Exon 5 of 6	ENSP00000354511.6	P21964-1
	COMT	ENST00000406520.7	TSL:1	c.597G>A	p.Pro199Pro	synonymous	Exon 5 of 6	ENSP00000385150.3	P21964-1
	COMT	ENST00000449653.5	TSL:1	c.447G>A	p.Pro149Pro	synonymous	Exon 3 of 4	ENSP00000416778.1	P21964-2

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6579 AN: 152172 Hom.: 219 Cov.: 33

Gnomad AFR AF: 0.0934

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0288

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.0644

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0297

GnomAD2 exomes AF: 0.0302 AC: 7592 AN: 251326 AF XY: 0.0282

Gnomad AFR exome AF: 0.0924

Gnomad AMR exome AF: 0.0267

Gnomad ASJ exome AF: 0.0205

Gnomad EAS exome AF: 0.0696

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.0217

Gnomad OTH exome AF: 0.0231

GnomAD4 exome AF: 0.0245 AC: 35875 AN: 1461674 Hom.: 580 Cov.: 33 AF XY: 0.0242 AC XY: 17580 AN XY: 727154

African (AFR) AF: 0.0934 AC: 3127 AN: 33480

American (AMR) AF: 0.0258 AC: 1152 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 561 AN: 26136

East Asian (EAS) AF: 0.0533 AC: 2116 AN: 39700

South Asian (SAS) AF: 0.0219 AC: 1890 AN: 86258

European-Finnish (FIN) AF: 0.0172 AC: 913 AN: 53214

Middle Eastern (MID) AF: 0.0260 AC: 150 AN: 5768

European-Non Finnish (NFE) AF: 0.0219 AC: 24302 AN: 1112004

Other (OTH) AF: 0.0276 AC: 1664 AN: 60394

GnomAD4 genome AF: 0.0433 AC: 6589 AN: 152290 Hom.: 219 Cov.: 33 AF XY: 0.0431 AC XY: 3207 AN XY: 74452

African (AFR) AF: 0.0933 AC: 3878 AN: 41548

American (AMR) AF: 0.0289 AC: 442 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 72 AN: 3468

East Asian (EAS) AF: 0.0645 AC: 334 AN: 5178

South Asian (SAS) AF: 0.0205 AC: 99 AN: 4832

European-Finnish (FIN) AF: 0.0203 AC: 216 AN: 10624

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0218 AC: 1481 AN: 68018

Other (OTH) AF: 0.0294 AC: 62 AN: 2112

Alfa AF: 0.0284 Hom.: 371

Bravo AF: 0.0462

Asia WGS AF: 0.0380 AC: 134 AN: 3478

EpiCase AF: 0.0215

EpiControl AF: 0.0223

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	-	Tramadol response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.3
DANN	Benign	0.78
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs769224; hg19: chr22-19951804; COSMIC: COSV52889936; COSMIC: COSV52889936;