22-19943901-A-AG

Variant names:

• chr22-19943901-A-AG
• rs5844402
• NM_000754.4:c.-92+2011dupG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000754.4(COMT):​c.-92+2011dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.010 (15 hom., cov: 0)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 2 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0102 (1550/151852) while in subpopulation AFR AF = 0.0345 (1427/41372). AF 95% confidence interval is 0.033. There are 15 homozygotes in GnomAd4. There are 736 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1550 AD gene.

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+2011dupG		intron	N/A	NP_000745.1	P21964-1
	COMT	NM_001362828.2		c.-386+2011dupG		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+2004_-92+2005insG		intron	N/A	ENSP00000354511.6	P21964-1
	COMT	ENST00000964897.1		c.-92+2004_-92+2005insG		intron	N/A	ENSP00000634956.1
	COMT	ENST00000678769.1		c.-92+2004_-92+2005insG		intron	N/A	ENSP00000503289.1	A0A7I2V370

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1546 AN: 151730 Hom.: 15 Cov.: 0

Gnomad AFR AF: 0.0345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00492

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00765

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

GnomAD4 genome AF: 0.0102 AC: 1550 AN: 151852 Hom.: 15 Cov.: 0 AF XY: 0.00992 AC XY: 736 AN XY: 74206

African (AFR) AF: 0.0345 AC: 1427 AN: 41372

American (AMR) AF: 0.00491 AC: 75 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67936

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00 Hom.: 631

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs5844402; hg19: chr22-19931424;