chr22-19961340-G-C

Position:

• chr22-19961340-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000754.4(COMT):​c.-1+51G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 152,196 control chromosomes in the GnomAD database, including 17,701 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 0.48 (17686 hom., cov: 34)
  • Exomes 𝑓: 0.52 (15 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0930

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COMT	NM_000754.4	c.-1+51G>C		intron_variant		ENST00000361682.11	NP_000745.1
COMT	NM_001135161.2	c.-1+51G>C		intron_variant			NP_001128633.1
COMT	NM_001135162.2	c.-1+51G>C		intron_variant			NP_001128634.1
COMT	NM_001362828.2	c.-295+51G>C		intron_variant			NP_001349757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11	c.-1+51G>C		intron_variant		1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72871 AN: 151978 Hom.: 17678 Cov.: 34

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.454

GnomAD4 exome AF: 0.520 AC: 52 AN: 100 Hom.: 15 AF XY: 0.527 AC XY: 39 AN XY: 74

Gnomad4 AFR exome AF: 0.00

Gnomad4 SAS exome AF: 0.667

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.524

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.479 AC: 72899 AN: 152096 Hom.: 17686 Cov.: 34 AF XY: 0.478 AC XY: 35553 AN XY: 74346

Gnomad4 AFR AF: 0.437

Gnomad4 AMR AF: 0.421

Gnomad4 ASJ AF: 0.465

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.475

Gnomad4 FIN AF: 0.551

Gnomad4 NFE AF: 0.522

Gnomad4 OTH AF: 0.451

Alfa AF: 0.370 Hom.: 1005

Bravo AF: 0.465

Asia WGS AF: 0.356 AC: 1238 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs165656; hg19: chr22-19948863;