rs4646316

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr22-19964609-C-A
• chr22-19964609-C-G
• chr22-19964609-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000754.4(COMT):​c.615+310C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000222 in 450,970 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.472
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.615+310C>A		intron_variant	Intron 5 of 5	ENST00000361682.11	NP_000745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11	c.615+310C>A		intron_variant	Intron 5 of 5	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000222 AC: 1 AN: 450970 Hom.: 0 Cov.: 0 AF XY: 0.00000420 AC XY: 1 AN XY: 237992

African (AFR) AF: 0.00 AC: 0 AN: 12528

American (AMR) AF: 0.00 AC: 0 AN: 19282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13758

East Asian (EAS) AF: 0.00 AC: 0 AN: 31148

South Asian (SAS) AF: 0.00 AC: 0 AN: 46002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1976

European-Non Finnish (NFE) AF: 0.00000369 AC: 1 AN: 270696

Other (OTH) AF: 0.00 AC: 0 AN: 26114

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.7
DANN	Benign	0.41
PhyloP100		-0.47

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;