chr22-19964609-C-T

Variant names:

• chr22-19964609-C-T
• rs4646316
• NM_000754.4:c.615+310C>T

Variant summary

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

The NM_000754.4(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 NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.472
• Publications: 71 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.297 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	NM_000754.4	MANE Select	c.615+310C>T		intron	N/A	NP_000745.1
	COMT	NM_001135161.2		c.615+310C>T		intron	N/A	NP_001128633.1
	COMT	NM_001135162.2		c.615+310C>T		intron	N/A	NP_001128634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.615+310C>T		intron	N/A	ENSP00000354511.6
	COMT	ENST00000406520.7	TSL:1	c.615+310C>T		intron	N/A	ENSP00000385150.3
	COMT	ENST00000449653.5	TSL:1	c.465+310C>T		intron	N/A	ENSP00000416778.1

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

African (AFR) AF: 0.198 AC: 2484 AN: 12522

American (AMR) AF: 0.168 AC: 3234 AN: 19282

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 3157 AN: 13756

East Asian (EAS) AF: 0.287 AC: 8927 AN: 31128

South Asian (SAS) AF: 0.147 AC: 6756 AN: 45990

European-Finnish (FIN) AF: 0.196 AC: 5788 AN: 29458

Middle Eastern (MID) AF: 0.226 AC: 447 AN: 1976

European-Non Finnish (NFE) AF: 0.240 AC: 64805 AN: 270580

Other (OTH) AF: 0.229 AC: 5975 AN: 26100

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

African (AFR) AF: 0.195 AC: 8082 AN: 41518

American (AMR) AF: 0.195 AC: 2978 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 853 AN: 3472

East Asian (EAS) AF: 0.309 AC: 1600 AN: 5170

South Asian (SAS) AF: 0.152 AC: 735 AN: 4828

European-Finnish (FIN) AF: 0.200 AC: 2122 AN: 10590

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16295 AN: 67970

Other (OTH) AF: 0.236 AC: 498 AN: 2108

Alfa AF: 0.230 Hom.: 14613

Bravo AF: 0.220

Asia WGS AF: 0.223 AC: 777 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.3
DANN	Benign	0.43
PhyloP100		-0.47
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: rs4646316; hg19: chr22-19952132;