rs6269

Variant names:

• chr22-19962429-A-G
• rs6269
• NM_000754.4:c.1-98A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-19962429-A-G
• chr22-19962429-A-T

Variant summary

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

The NM_001362828.2(COMT):​c.-98A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 1,521,518 control chromosomes in the GnomAD database, including 117,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (10887 hom., cov: 33)
  • Exomes 𝑓: 0.39 (106561 hom.)
• Consequence: COMT NM_001362828.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.47
• Publications: 245 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=-0.91).
• BP6: Variant 22-19962429-A-G is Benign according to our data. Variant chr22-19962429-A-G is described in ClinVar as Benign. ClinVar VariationId is 1275060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001362828.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	NM_000754.4	MANE Select	c.1-98A>G		intron	N/A	NP_000745.1
	COMT	NM_001362828.2		c.-98A>G		5_prime_UTR	Exon 3 of 6	NP_001349757.1
	COMT	NM_001135161.2		c.1-98A>G		intron	N/A	NP_001128633.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.1-98A>G		intron	N/A	ENSP00000354511.6
	COMT	ENST00000406520.7	TSL:1	c.1-98A>G		intron	N/A	ENSP00000385150.3
	COMT	ENST00000964896.1		c.-98A>G		5_prime_UTR	Exon 3 of 7	ENSP00000634955.1

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57285 AN: 152008 Hom.: 10884 Cov.: 33

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.396

GnomAD4 exome AF: 0.392 AC: 536868 AN: 1369392 Hom.: 106561 Cov.: 30 AF XY: 0.392 AC XY: 263406 AN XY: 672754

African (AFR) AF: 0.368 AC: 11627 AN: 31628

American (AMR) AF: 0.244 AC: 8995 AN: 36810

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 11324 AN: 24486

East Asian (EAS) AF: 0.295 AC: 10599 AN: 35886

South Asian (SAS) AF: 0.339 AC: 26308 AN: 77622

European-Finnish (FIN) AF: 0.325 AC: 11157 AN: 34330

Middle Eastern (MID) AF: 0.435 AC: 1741 AN: 4004

European-Non Finnish (NFE) AF: 0.405 AC: 432510 AN: 1067646

Other (OTH) AF: 0.397 AC: 22607 AN: 56980

GnomAD4 genome AF: 0.377 AC: 57316 AN: 152126 Hom.: 10887 Cov.: 33 AF XY: 0.372 AC XY: 27645 AN XY: 74372

African (AFR) AF: 0.375 AC: 15570 AN: 41494

American (AMR) AF: 0.331 AC: 5056 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1648 AN: 3470

East Asian (EAS) AF: 0.324 AC: 1671 AN: 5160

South Asian (SAS) AF: 0.330 AC: 1591 AN: 4824

European-Finnish (FIN) AF: 0.309 AC: 3272 AN: 10598

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.401 AC: 27263 AN: 67968

Other (OTH) AF: 0.396 AC: 838 AN: 2114

Alfa AF: 0.383 Hom.: 21084

Bravo AF: 0.378

Asia WGS AF: 0.327 AC: 1141 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.68
DANN	Benign	0.39
PhyloP100		-2.5
PromoterAI		0.19	Neutral
Mutation Taster		=300/0	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: rs6269; hg19: chr22-19949952; COSMIC: COSV52891062; COSMIC: COSV52891062;