chr22-19964609-C-T

Position:

• chr22-19964609-C-T

Variant summary

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

The ENST00000361682.11(COMT):​c.615+310C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 602,952 control chromosomes in the GnomAD database, including 15,749 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 0.22 (3828 hom., cov: 33)
  • Exomes 𝑓: 0.23 (11921 hom.)
• Consequence: COMT ENST00000361682.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.472

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COMT	NM_000754.4	c.615+310C>T		intron_variant		ENST00000361682.11	NP_000745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11	c.615+310C>T		intron_variant		1	NM_000754.4	ENSP00000354511	P2

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33372 AN: 152042 Hom.: 3832 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.238

GnomAD4 exome AF: 0.225 AC: 101573 AN: 450792 Hom.: 11921 Cov.: 0 AF XY: 0.221 AC XY: 52683 AN XY: 237878

Gnomad4 AFR exome AF: 0.198

Gnomad4 AMR exome AF: 0.168

Gnomad4 ASJ exome AF: 0.230

Gnomad4 EAS exome AF: 0.287

Gnomad4 SAS exome AF: 0.147

Gnomad4 FIN exome AF: 0.196

Gnomad4 NFE exome AF: 0.240

Gnomad4 OTH exome AF: 0.229

GnomAD4 genome AF: 0.219 AC: 33377 AN: 152160 Hom.: 3828 Cov.: 33 AF XY: 0.219 AC XY: 16282 AN XY: 74382

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.246

Gnomad4 EAS AF: 0.309

Gnomad4 SAS AF: 0.152

Gnomad4 FIN AF: 0.200

Gnomad4 NFE AF: 0.240

Gnomad4 OTH AF: 0.236

Alfa AF: 0.233 Hom.: 6426

Bravo AF: 0.220

Asia WGS AF: 0.223 AC: 777 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.3
DANN	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs4646316; hg19: chr22-19952132;