rs201836020

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr16-1229731-C-A
• chr16-1229731-C-G
• chr16-1229731-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_024164.6(TPSB2):​c.68G>T​(p.Gly23Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G23A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.33 (57 hom., cov: 25)
  • Exomes 𝑓: 0.22 (609 hom.)
  • Failed GnomAD Quality Control
• Consequence: TPSB2 NM_024164.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002231419).
• BP6: Variant 16-1229731-C-A is Benign according to our data. Variant chr16-1229731-C-A is described in ClinVar as Benign. ClinVar VariationId is 403562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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>T	p.Gly23Val	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>T	p.Gly23Val	missense	Exon 3 of 6	ENSP00000482743.1	P20231
	TPSB2	ENST00000612142.2	TSL:1	c.89G>T	p.Gly30Val	missense	Exon 2 of 5	ENSP00000478695.1	A0A087WUI4
	TPSB2	ENST00000611196.4	TSL:1	n.68G>T		non_coding_transcript_exon	Exon 3 of 8	ENSP00000484461.1	A0A087X1U0

Frequencies

GnomAD3 genomes AF: 0.328 AC: 42146 AN: 128340 Hom.: 57 Cov.: 25

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.286

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.326

GnomAD2 exomes AF: 0.241 AC: 37070 AN: 153848 AF XY: 0.240

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.251

Gnomad EAS exome AF: 0.361

Gnomad FIN exome AF: 0.346

Gnomad NFE exome AF: 0.233

Gnomad OTH exome AF: 0.240

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.225 AC: 234565 AN: 1043948 Hom.: 609 Cov.: 71 AF XY: 0.235 AC XY: 123824 AN XY: 527044

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

African (AFR) AF: 0.182 AC: 4511 AN: 24732

American (AMR) AF: 0.282 AC: 10022 AN: 35504

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 6156 AN: 20806

East Asian (EAS) AF: 0.436 AC: 15189 AN: 34852

South Asian (SAS) AF: 0.296 AC: 20255 AN: 68476

European-Finnish (FIN) AF: 0.413 AC: 18175 AN: 44034

Middle Eastern (MID) AF: 0.239 AC: 833 AN: 3486

European-Non Finnish (NFE) AF: 0.193 AC: 147993 AN: 767264

Other (OTH) AF: 0.255 AC: 11431 AN: 44794

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.328 AC: 42166 AN: 128432 Hom.: 57 Cov.: 25 AF XY: 0.330 AC XY: 20686 AN XY: 62726

African (AFR) AF: 0.277 AC: 9347 AN: 33716

American (AMR) AF: 0.307 AC: 4004 AN: 13026

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 985 AN: 3080

East Asian (EAS) AF: 0.440 AC: 1849 AN: 4202

South Asian (SAS) AF: 0.325 AC: 1243 AN: 3824

European-Finnish (FIN) AF: 0.421 AC: 3801 AN: 9026

Middle Eastern (MID) AF: 0.278 AC: 69 AN: 248

European-Non Finnish (NFE) AF: 0.341 AC: 20018 AN: 58702

Other (OTH) AF: 0.323 AC: 581 AN: 1798

Alfa AF: 0.228 Hom.: 40

ExAC AF: 0.243 AC: 29238

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	11
DANN	Benign	0.96
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.50	T
PhyloP100		0.065
PrimateAI	Uncertain	0.64	T
Sift4G	Benign	0.33	T
Vest4		0.10
ClinPred		0.019	T
GERP RS		0.77
PromoterAI		-0.042	Neutral
gMVP		0.60
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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; COSMIC: COSV52352433; COSMIC: COSV52352433;