16-1229731-C-G

Variant names:

• chr16-1229731-C-G
• rs201836020
• NM_024164.6:c.68G>C

Variant summary

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

The NM_024164.6(TPSB2):​c.68G>C​(p.Gly23Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000198 in 1,512,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G23V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TPSB2 NM_024164.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0650
• Publications: 14 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: 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=0.1244711).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024164.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPSB2	NM_024164.6	MANE Select	c.68G>C	p.Gly23Ala	missense	Exon 3 of 6	NP_077078.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPSB2	ENST00000606293.5	TSL:1 MANE Select	c.68G>C	p.Gly23Ala	missense	Exon 3 of 6	ENSP00000482743.1	P20231
	TPSB2	ENST00000612142.2	TSL:1	c.89G>C	p.Gly30Ala	missense	Exon 2 of 5	ENSP00000478695.1	A0A087WUI4
	TPSB2	ENST00000611196.4	TSL:1	n.68G>C		non_coding_transcript_exon	Exon 3 of 8	ENSP00000484461.1	A0A087X1U0

Frequencies

GnomAD3 genomes AF: 0.00000695 AC: 1 AN: 143978 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

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: 0.0000151

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1368858 Hom.: 0 Cov.: 71 AF XY: 0.00 AC XY: 0 AN XY: 681554

African (AFR) AF: 0.00 AC: 0 AN: 30842

American (AMR) AF: 0.00 AC: 0 AN: 40416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23960

East Asian (EAS) AF: 0.00 AC: 0 AN: 38992

South Asian (SAS) AF: 0.00 AC: 0 AN: 80002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000192 AC: 2 AN: 1043058

Other (OTH) AF: 0.00 AC: 0 AN: 56810

GnomAD4 genome AF: 0.00000695 AC: 1 AN: 143978 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 70144

African (AFR) AF: 0.00 AC: 0 AN: 37360

American (AMR) AF: 0.00 AC: 0 AN: 14678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 4584

South Asian (SAS) AF: 0.00 AC: 0 AN: 4448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66230

Other (OTH) AF: 0.00 AC: 0 AN: 1980

Alfa AF: 0.00 Hom.: 40

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	10
DANN	Benign	0.90
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.56	T
PhyloP100		0.065
PrimateAI	Uncertain	0.64	T
Sift4G	Benign	0.74	T
Vest4		0.25
MutPred		0.34		Gain of glycosylation at P20 (P = 0.1033)
MVP		0.14
ClinPred		0.37	T
GERP RS		0.77
PromoterAI		-0.024	Neutral
gMVP		0.51

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: rs201836020; hg19: chr16-1279732;