22-19962627-G-C

Variant names:

• chr22-19962627-G-C
• rs6270
• NM_000754.4:c.101G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000754.4(COMT):​c.101G>C​(p.Cys34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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)
• Consequence: COMT NM_000754.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0720
• Publications: 10 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09484869).

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.101G>C	p.Cys34Ser	missense	Exon 3 of 6	NP_000745.1
	COMT	NM_001135161.2		c.101G>C	p.Cys34Ser	missense	Exon 3 of 6	NP_001128633.1
	COMT	NM_001135162.2		c.101G>C	p.Cys34Ser	missense	Exon 3 of 6	NP_001128634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.101G>C	p.Cys34Ser	missense	Exon 3 of 6	ENSP00000354511.6
	COMT	ENST00000406520.7	TSL:1	c.101G>C	p.Cys34Ser	missense	Exon 3 of 6	ENSP00000385150.3
	COMT	ENST00000449653.5	TSL:1	c.-50G>C		5_prime_UTR	Exon 1 of 4	ENSP00000416778.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.7
DANN	Benign	0.77
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.072
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.12
Sift	Benign	0.13	T
Sift4G	Benign	0.074	T
Polyphen		0.0090	B
Vest4		0.18
MutPred		0.14		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.58
MPC		0.32
ClinPred		0.085	T
GERP RS		-2.0
PromoterAI		0.0032	Neutral
Varity_R		0.033
gMVP		0.85
Mutation Taster		=90/10	polymorphism

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: rs6270; hg19: chr22-19950150;