chr16-1228812-G-A

Variant names:

• chr16-1228812-G-A
• rs781452222
• NM_024164.6:c.666C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_024164.6(TPSB2):​c.666C>T​(p.Gly222Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,293,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000048 (0 hom., cov: 6)
  • Exomes 𝑓: 0.000013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TPSB2 NM_024164.6 splice_region, synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -13.4
• Publications: 0 publications found

Genes affected

TPSB2 (HGNC:14120): (tryptase beta 2) Tryptases comprise a family of trypsin-like serine proteases, the peptidase family S1. Tryptases are enzymatically active only as heparin-stabilized tetramers, and they are resistant to all known endogenous proteinase inhibitors. Several tryptase genes are clustered on chromosome 16p13.3. These genes are characterized by several distinct features. They have a highly conserved 3' UTR and contain tandem repeat sequences at the 5' flank and 3' UTR which are thought to play a role in regulation of the mRNA stability. These genes have an intron immediately upstream of the initiator Met codon, which separates the site of transcription initiation from protein coding sequence. This feature is characteristic of tryptases but is unusual in other genes. The alleles of this gene exhibit an unusual amount of sequence variation, such that the alleles were once thought to represent two separate genes, beta II and beta III. Beta tryptases appear to be the main isoenzymes expressed in mast cells, whereas in basophils, alpha-tryptases predominate. Tryptases have been implicated as mediators in the pathogenesis of asthma and other allergic and inflammatory disorders. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-1228812-G-A is Benign according to our data. Variant chr16-1228812-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2645885.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-13.4 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPSB2	NM_024164.6	c.666C>T	p.Gly222Gly	splice_region_variant, synonymous_variant	Exon 6 of 6	ENST00000606293.5	NP_077078.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPSB2	ENST00000606293.5	c.666C>T	p.Gly222Gly	splice_region_variant, synonymous_variant	Exon 6 of 6	1	NM_024164.6	ENSP00000482743.1

Frequencies

GnomAD3 genomes AF: 0.0000476 AC: 2 AN: 42044 Hom.: 0 Cov.: 6

Gnomad AFR AF: 0.000231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000291 AC: 4 AN: 137408 AF XY: 0.0000413

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.0000424

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000364

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 17 AN: 1293484 Hom.: 0 Cov.: 22 AF XY: 0.0000142 AC XY: 9 AN XY: 635142

African (AFR) AF: 0.00 AC: 0 AN: 28046

American (AMR) AF: 0.0000602 AC: 2 AN: 33196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20868

East Asian (EAS) AF: 0.00 AC: 0 AN: 33732

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3624

European-Non Finnish (NFE) AF: 0.00000996 AC: 10 AN: 1004226

Other (OTH) AF: 0.0000758 AC: 4 AN: 52778

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000476 AC: 2 AN: 42044 Hom.: 0 Cov.: 6 AF XY: 0.0000555 AC XY: 1 AN XY: 18028

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000231 AC: 2 AN: 8660

American (AMR) AF: 0.00 AC: 0 AN: 3760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1186

East Asian (EAS) AF: 0.00 AC: 0 AN: 1550

South Asian (SAS) AF: 0.00 AC: 0 AN: 750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 22368

Other (OTH) AF: 0.00 AC: 0 AN: 536

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TPSB2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.3
DANN	Benign	0.92
PhyloP100		-13
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs781452222; hg19: chr16-1278812;