chr22-19941996-G-A

Variant names:

• chr22-19941996-G-A
• rs45454096
• NM_000754.4:c.-92+99G>A

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.-92+99G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 490,386 control chromosomes in the GnomAD database, including 466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (142 hom., cov: 32)
  • Exomes 𝑓: 0.039 (324 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.149
• Publications: 4 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]

TXNRD2 (HGNC:18155): (thioredoxin reductase 2) The protein encoded by this gene belongs to the pyridine nucleotide-disulfide oxidoreductase family, and is a member of the thioredoxin (Trx) system. Three thioredoxin reductase (TrxR) isozymes are found in mammals. TrxRs are selenocysteine-containing flavoenzymes, which reduce thioredoxins, as well as other substrates, and play a key role in redox homoeostasis. This gene encodes a mitochondrial form important for scavenging reactive oxygen species in mitochondria. It functions as a homodimer containing FAD, and selenocysteine (Sec) at the active site. Sec is encoded by UGA codon that normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Alternatively spliced transcript variants encoding different isoforms, including a few localized in the cytosol and some lacking the C-terminal Sec residue, have been found for this gene. [provided by RefSeq, Jun 2017]

TXNRD2 Gene-Disease associations (from GenCC):

• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial glucocorticoid deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• glucocorticoid deficiency 5

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-19941996-G-A is Benign according to our data. Variant chr22-19941996-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 678642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.094 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.-92+99G>A		intron	N/A	NP_000745.1
	COMT	NM_001362828.2		c.-386+99G>A		intron	N/A	NP_001349757.1
	TXNRD2	NM_006440.5	MANE Select	c.-193C>T		upstream_gene	N/A	NP_006431.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.-92+99G>A		intron	N/A	ENSP00000354511.6
	COMT	ENST00000678769.1		c.-92+99G>A		intron	N/A	ENSP00000503289.1
	COMT	ENST00000428707.2	TSL:3	c.-92+99G>A		intron	N/A	ENSP00000387695.2

Frequencies

GnomAD3 genomes AF: 0.0416 AC: 6320 AN: 152068 Hom.: 142 Cov.: 32

Gnomad AFR AF: 0.0421

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.0533

Gnomad ASJ AF: 0.0292

Gnomad EAS AF: 0.0184

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.0574

GnomAD4 exome AF: 0.0389 AC: 13163 AN: 338204 Hom.: 324 Cov.: 5 AF XY: 0.0410 AC XY: 7208 AN XY: 175762

African (AFR) AF: 0.0367 AC: 264 AN: 7194

American (AMR) AF: 0.0533 AC: 360 AN: 6754

Ashkenazi Jewish (ASJ) AF: 0.0287 AC: 276 AN: 9608

East Asian (EAS) AF: 0.0159 AC: 334 AN: 20964

South Asian (SAS) AF: 0.0886 AC: 1873 AN: 21146

European-Finnish (FIN) AF: 0.0228 AC: 551 AN: 24184

Middle Eastern (MID) AF: 0.0283 AC: 42 AN: 1482

European-Non Finnish (NFE) AF: 0.0382 AC: 8680 AN: 227180

Other (OTH) AF: 0.0398 AC: 783 AN: 19692

GnomAD4 genome AF: 0.0416 AC: 6326 AN: 152182 Hom.: 142 Cov.: 32 AF XY: 0.0411 AC XY: 3061 AN XY: 74410

African (AFR) AF: 0.0421 AC: 1749 AN: 41532

American (AMR) AF: 0.0533 AC: 816 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0292 AC: 101 AN: 3464

East Asian (EAS) AF: 0.0184 AC: 95 AN: 5160

South Asian (SAS) AF: 0.101 AC: 490 AN: 4830

European-Finnish (FIN) AF: 0.0197 AC: 209 AN: 10598

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0399 AC: 2715 AN: 67984

Other (OTH) AF: 0.0573 AC: 121 AN: 2112

Alfa AF: 0.0360 Hom.: 18

Bravo AF: 0.0430

Asia WGS AF: 0.0580 AC: 201 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.0
DANN	Benign	0.71
PhyloP100		0.15
PromoterAI		-0.039	Neutral
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: rs45454096; hg19: chr22-19929519;