chr22-19942586-T-C

Variant names:

• chr22-19942586-T-C
• rs737866
• NM_000754.4:c.-92+689T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000754.4(COMT):​c.-92+689T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 152,112 control chromosomes in the GnomAD database, including 4,397 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4397 hom., cov: 32)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.446
• Publications: 57 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.275 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.-92+689T>C		intron	N/A	NP_000745.1	P21964-1
	COMT	NM_001362828.2		c.-386+689T>C		intron	N/A	NP_001349757.1	P21964-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.-92+689T>C		intron	N/A	ENSP00000354511.6	P21964-1
	COMT	ENST00000964897.1		c.-92+689T>C		intron	N/A	ENSP00000634956.1
	COMT	ENST00000678769.1		c.-92+689T>C		intron	N/A	ENSP00000503289.1	A0A7I2V370

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35365 AN: 151994 Hom.: 4396 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.427

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.256

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.233 AC: 35379 AN: 152112 Hom.: 4397 Cov.: 32 AF XY: 0.230 AC XY: 17139 AN XY: 74356

African (AFR) AF: 0.149 AC: 6185 AN: 41512

American (AMR) AF: 0.220 AC: 3359 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 1483 AN: 3472

East Asian (EAS) AF: 0.272 AC: 1403 AN: 5160

South Asian (SAS) AF: 0.262 AC: 1261 AN: 4804

European-Finnish (FIN) AF: 0.186 AC: 1974 AN: 10596

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.278 AC: 18924 AN: 67968

Other (OTH) AF: 0.257 AC: 542 AN: 2110

Alfa AF: 0.268 Hom.: 24526

Bravo AF: 0.228

Asia WGS AF: 0.271 AC: 943 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.4
DANN	Benign	0.78
PhyloP100		0.45
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: rs737866; hg19: chr22-19930109;