16-1221970-C-T

Variant names:

• chr16-1221970-C-T
• rs58623186
• NM_012467.4:c.784G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012467.4(TPSG1):​c.784G>A​(p.Val262Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,612,320 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (45 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (39 hom.)
• Consequence: TPSG1 NM_012467.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.90

Genes affected

TPSG1 (HGNC:14134): (tryptase gamma 1) 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. There is uncertainty regarding the number of genes in this cluster. Currently four functional genes - alpha I, beta I, beta II and gamma I - have been identified. And beta I has an allelic variant named alpha II, beta II has an allelic variant beta III, also gamma I has an allelic variant gamma II. Beta tryptases appear to be the main isoenzymes expressed in mast cells; whereas in basophils, alpha-tryptases predominant. This gene differs from other members of the tryptase gene family in that it has C-terminal hydrophobic domain, which may serve as a membrane anchor. Tryptases have been implicated as mediators in the pathogenesis of asthma and other allergic and inflammatory disorders. [provided by RefSeq, Jul 2008]

CACNA1H (HGNC:1395): (calcium voltage-gated channel subunit alpha1 H) This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants, encoding different isoforms, have been characterized for the gene described here. Studies suggest certain mutations in this gene lead to childhood absence epilepsy (CAE). [provided by RefSeq, Jul 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.004752189).
• BP6: Variant 16-1221970-C-T is Benign according to our data. Variant chr16-1221970-C-T is described in ClinVar as [Benign]. Clinvar id is 786632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0129 (1967/152286) while in subpopulation AFR AF = 0.045 (1871/41556). AF 95% confidence interval is 0.0433. There are 45 homozygotes in GnomAd4. There are 965 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPSG1	NM_012467.4	c.784G>A	p.Val262Met	missense_variant	Exon 6 of 6	ENST00000234798.5	NP_036599.4
CACNA1H	NM_021098.3	c.*976C>T		downstream_gene_variant		ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPSG1	ENST00000234798.5	c.784G>A	p.Val262Met	missense_variant	Exon 6 of 6	1	NM_012467.4	ENSP00000234798.4
CACNA1H	ENST00000348261.11	c.*976C>T		downstream_gene_variant		1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.*976C>T		downstream_gene_variant		1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.*976C>T		downstream_gene_variant		5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.*3086C>T		downstream_gene_variant		5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*5856C>T		downstream_gene_variant		5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1960 AN: 152168 Hom.: 45 Cov.: 34

Gnomad AFR AF: 0.0450

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00317 AC: 786 AN: 247630 AF XY: 0.00234

Gnomad AFR exome AF: 0.0438

Gnomad AMR exome AF: 0.00221

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000117

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00128 AC: 1862 AN: 1460034 Hom.: 39 Cov.: 77 AF XY: 0.00107 AC XY: 775 AN XY: 726226

Gnomad4 AFR exome AF: 0.0433 AC: 1448 AN: 33476

Gnomad4 AMR exome AF: 0.00289 AC: 129 AN: 44688

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26096

Gnomad4 EAS exome AF: 0.0000504 AC: 2 AN: 39688

Gnomad4 SAS exome AF: 0.0000464 AC: 4 AN: 86210

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52074

Gnomad4 NFE exome AF: 0.0000927 AC: 103 AN: 1111688

Gnomad4 Remaining exome AF: 0.00282 AC: 170 AN: 60346

GnomAD4 genome AF: 0.0129 AC: 1967 AN: 152286 Hom.: 45 Cov.: 34 AF XY: 0.0130 AC XY: 965 AN XY: 74462

Gnomad4 AFR AF: 0.0450 AC: 0.0450236 AN: 0.0450236

Gnomad4 AMR AF: 0.00379 AC: 0.00378986 AN: 0.00378986

Gnomad4 ASJ AF: 0.000288 AC: 0.000288018 AN: 0.000288018

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000221 AC: 0.000220549 AN: 0.000220549

Gnomad4 OTH AF: 0.0104 AC: 0.0104167 AN: 0.0104167

Alfa AF: 0.00604 Hom.: 23

Bravo AF: 0.0148

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0446 AC: 196

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00385 AC: 467

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 13, 2017

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	2.7
DANN	Uncertain	0.99
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.014	N
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.32	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.26
Sift	Benign	0.18	T
Sift4G	Benign	0.22	T
Vest4		0.15
MVP		0.63
MPC		0.0098
ClinPred		0.015	T
GERP RS		0.65
gMVP		0.33
Mutation Taster		=94/6	polymorphism

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

Publications

LitVar

Other links and lift over

dbSNP: rs58623186; hg19: chr16-1271970;