rs2239393

Variant names:

• chr22-19962905-A-G
• rs2239393
• NM_000754.4:c.289+90A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000754.4(COMT):​c.289+90A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 1,468,990 control chromosomes in the GnomAD database, including 114,894 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11464 hom., cov: 33)
  • Exomes 𝑓: 0.39 (103430 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -1.77
• Publications: 48 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 22-19962905-A-G is Benign according to our data. Variant chr22-19962905-A-G is described in ClinVar as Benign. ClinVar VariationId is 829771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.408 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.289+90A>G		intron	N/A	NP_000745.1	P21964-1
	COMT	NM_001135161.2		c.289+90A>G		intron	N/A	NP_001128633.1	P21964-1
	COMT	NM_001135162.2		c.289+90A>G		intron	N/A	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.289+90A>G		intron	N/A	ENSP00000354511.6	P21964-1
	COMT	ENST00000406520.7	TSL:1	c.289+90A>G		intron	N/A	ENSP00000385150.3	P21964-1
	COMT	ENST00000449653.5	TSL:1	c.139+90A>G		intron	N/A	ENSP00000416778.1	P21964-2

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58883 AN: 151854 Hom.: 11461 Cov.: 33

Gnomad AFR AF: 0.414

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.405

GnomAD4 exome AF: 0.394 AC: 519021 AN: 1317018 Hom.: 103430 Cov.: 21 AF XY: 0.394 AC XY: 253892 AN XY: 644606

African (AFR) AF: 0.407 AC: 12305 AN: 30214

American (AMR) AF: 0.252 AC: 8006 AN: 31740

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 9524 AN: 20390

East Asian (EAS) AF: 0.299 AC: 11332 AN: 37918

South Asian (SAS) AF: 0.339 AC: 23735 AN: 70038

European-Finnish (FIN) AF: 0.327 AC: 15258 AN: 46724

Middle Eastern (MID) AF: 0.416 AC: 1783 AN: 4288

European-Non Finnish (NFE) AF: 0.407 AC: 415251 AN: 1021126

Other (OTH) AF: 0.400 AC: 21827 AN: 54580

GnomAD4 genome AF: 0.388 AC: 58919 AN: 151972 Hom.: 11464 Cov.: 33 AF XY: 0.382 AC XY: 28381 AN XY: 74278

African (AFR) AF: 0.414 AC: 17143 AN: 41440

American (AMR) AF: 0.333 AC: 5099 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1648 AN: 3468

East Asian (EAS) AF: 0.323 AC: 1664 AN: 5152

South Asian (SAS) AF: 0.330 AC: 1585 AN: 4808

European-Finnish (FIN) AF: 0.310 AC: 3279 AN: 10578

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.401 AC: 27240 AN: 67920

Other (OTH) AF: 0.405 AC: 853 AN: 2108

Alfa AF: 0.395 Hom.: 46564

Bravo AF: 0.390

Asia WGS AF: 0.329 AC: 1147 AN: 3478

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	-0.90
CADD	Benign	0.19
DANN	Benign	0.37
PhyloP100		-1.8
PromoterAI		-0.0054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2239393; hg19: chr22-19950428; COSMIC: COSV52890338; COSMIC: COSV52890338;