chr22-19964374-G-C

Variant names:

• chr22-19964374-G-C
• rs4646315
• NM_000754.4:c.615+75G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000754.4(COMT):​c.615+75G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,604,012 control chromosomes in the GnomAD database, including 29,376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2595 hom., cov: 33)
  • Exomes 𝑓: 0.19 (26781 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.261
• Publications: 21 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045391023).
• BP6: Variant 22-19964374-G-C is Benign according to our data. Variant chr22-19964374-G-C is described in ClinVar as Benign. ClinVar VariationId is 828955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.228 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+75G>C		intron	N/A	NP_000745.1
	COMT	NM_001135161.2		c.615+75G>C		intron	N/A	NP_001128633.1
	COMT	NM_001135162.2		c.615+75G>C		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+75G>C		intron	N/A	ENSP00000354511.6
	COMT	ENST00000406520.7	TSL:1	c.615+75G>C		intron	N/A	ENSP00000385150.3
	COMT	ENST00000449653.5	TSL:1	c.465+75G>C		intron	N/A	ENSP00000416778.1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27352 AN: 152112 Hom.: 2594 Cov.: 33

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.201 AC: 48457 AN: 240914 AF XY: 0.201

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.117

Gnomad FIN exome AF: 0.298

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.188 AC: 273449 AN: 1451782 Hom.: 26781 Cov.: 30 AF XY: 0.190 AC XY: 137013 AN XY: 722302

African (AFR) AF: 0.145 AC: 4843 AN: 33302

American (AMR) AF: 0.239 AC: 10475 AN: 43872

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 3011 AN: 25990

East Asian (EAS) AF: 0.122 AC: 4820 AN: 39500

South Asian (SAS) AF: 0.243 AC: 20799 AN: 85664

European-Finnish (FIN) AF: 0.297 AC: 15549 AN: 52388

Middle Eastern (MID) AF: 0.179 AC: 1031 AN: 5756

European-Non Finnish (NFE) AF: 0.183 AC: 202142 AN: 1105220

Other (OTH) AF: 0.179 AC: 10779 AN: 60090

GnomAD4 genome AF: 0.180 AC: 27361 AN: 152230 Hom.: 2595 Cov.: 33 AF XY: 0.184 AC XY: 13656 AN XY: 74414

African (AFR) AF: 0.146 AC: 6065 AN: 41554

American (AMR) AF: 0.198 AC: 3019 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 401 AN: 3470

East Asian (EAS) AF: 0.122 AC: 631 AN: 5172

South Asian (SAS) AF: 0.240 AC: 1158 AN: 4826

European-Finnish (FIN) AF: 0.289 AC: 3066 AN: 10594

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12410 AN: 68012

Other (OTH) AF: 0.157 AC: 332 AN: 2112

Alfa AF: 0.178 Hom.: 796

Bravo AF: 0.171

TwinsUK AF: 0.180 AC: 669

ALSPAC AF: 0.186 AC: 715

ExAC AF: 0.196 AC: 23739

Asia WGS AF: 0.168 AC: 587 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Tramadol response Other:1

Apr 28, 2018

Bruce Budowle Laboratory, University of North Texas Health Science Center

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.3
DANN	Benign	0.95
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.26
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.080
Sift	Uncertain	0.017	D
Sift4G	Benign	0.078	T
Polyphen		0.0010	B
Vest4		0.021
MutPred		0.19		Loss of ubiquitination at K230 (P = 0.0011)
ClinPred		0.0032	T
GERP RS		-1.9
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: rs4646315; hg19: chr22-19951897; COSMIC: COSV52889132; COSMIC: COSV52889132;