16-1221890-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_012467.4(TPSG1):c.864C>A(p.Phe288Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.507 in 1,610,564 control chromosomes in the GnomAD database, including 213,290 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.55 ( 23373 hom., cov: 33)

Exomes 𝑓: 0.50 ( 189917 hom. )

Consequence

TPSG1
NM_012467.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.412

Publications

27 publications found

Variant links:

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]

TPSG1 links:

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]

CACNA1H Gene-Disease associations (from GenCC):

hyperaldosteronism, familial, type IV
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
childhood absence epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
epilepsy, childhood absence, susceptibility to, 6
Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

CACNA1H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.528061E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012467.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TPSG1	NM_012467.4	MANE Select	c.864C>A	p.Phe288Leu	missense	Exon 6 of 6	NP_036599.4
CACNA1H	NM_021098.3	MANE Select	c.*896G>T		downstream_gene	N/A	NP_066921.2
CACNA1H	NM_001005407.2		c.*896G>T		downstream_gene	N/A	NP_001005407.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TPSG1	ENST00000234798.5	TSL:1 MANE Select	c.864C>A	p.Phe288Leu	missense	Exon 6 of 6	ENSP00000234798.4
CACNA1H	ENST00000711486.1		n.*896G>T		non_coding_transcript_exon	Exon 35 of 37	ENSP00000518775.1
CACNA1H	ENST00000711487.1		n.*896G>T		non_coding_transcript_exon	Exon 35 of 36	ENSP00000518776.1

Frequencies

GnomAD3 genomes

AF:

0.546

AC:

82987

AN:

151868

Hom.:

23353

Cov.:

show subpopulations

Gnomad AFR

AF:

0.594

Gnomad AMI

AF:

0.404

Gnomad AMR

AF:

0.614

Gnomad ASJ

AF:

0.505

Gnomad EAS

AF:

0.861

Gnomad SAS

AF:

0.486

Gnomad FIN

AF:

0.632

Gnomad MID

AF:

0.535

Gnomad NFE

AF:

0.474

Gnomad OTH

AF:

0.534

GnomAD2 exomes

AF:

0.555

AC:

136801

AN:

246302

AF XY:

0.543

show subpopulations

Gnomad AFR exome

AF:

0.592

Gnomad AMR exome

AF:

0.681

Gnomad ASJ exome

AF:

0.501

Gnomad EAS exome

AF:

0.872

Gnomad FIN exome

AF:

0.613

Gnomad NFE exome

AF:

0.477

Gnomad OTH exome

AF:

0.523

GnomAD4 exome

AF:

0.503

AC:

733918

AN:

1458576

Hom.:

189917

Cov.:

AF XY:

0.500

AC XY:

363036

AN XY:

725364

show subpopulations

African (AFR)

AF:

0.600

AC:

20066

AN:

33448

American (AMR)

AF:

0.671

AC:

29867

AN:

44484

Ashkenazi Jewish (ASJ)

AF:

0.502

AC:

13069

AN:

26038

East Asian (EAS)

AF:

0.886

AC:

35135

AN:

39650

South Asian (SAS)

AF:

0.473

AC:

40740

AN:

86076

European-Finnish (FIN)

AF:

0.606

AC:

31538

AN:

52028

Middle Eastern (MID)

AF:

0.527

AC:

3034

AN:

5756

European-Non Finnish (NFE)

AF:

0.477

AC:

529528

AN:

1110822

Other (OTH)

AF:

0.513

AC:

30941

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

21382

42763

64145

85526

106908

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15916

31832

47748

63664

79580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.546

AC:

83042

AN:

151988

Hom.:

23373

Cov.:

AF XY:

0.556

AC XY:

41287

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.593

AC:

24586

AN:

41440

American (AMR)

AF:

0.614

AC:

9395

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.505

AC:

1751

AN:

3468

East Asian (EAS)

AF:

0.860

AC:

4439

AN:

5160

South Asian (SAS)

AF:

0.485

AC:

2332

AN:

4812

European-Finnish (FIN)

AF:

0.632

AC:

6682

AN:

10578

Middle Eastern (MID)

AF:

0.520

AC:

153

AN:

294

European-Non Finnish (NFE)

AF:

0.474

AC:

32198

AN:

67926

Other (OTH)

AF:

0.541

AC:

1138

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1850

3700

5550

7400

9250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

718

1436

2154

2872

3590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.497

Hom.:

74505

Bravo

AF:

0.553

TwinsUK

AF:

0.464

AC:

1722

ALSPAC

AF:

0.493

AC:

1900

ESP6500AA

AF:

0.592

AC:

2595

ESP6500EA

AF:

0.478

AC:

4112

ExAC

AF:

0.542

AC:

65514

Asia WGS

AF:

0.674

AC:

2343

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.53

CADD

Benign

8.2

(source)

DANN

Benign

0.68

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.42

MetaRNN

Benign

9.5e-7

MetaSVM

Benign

-0.96

PhyloP100

0.41

PrimateAI

Benign

0.32

PROVEAN

Benign

0.33

REVEL

Benign

0.12

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.019

MutPred

0.47

Gain of helix (P = 0.0696)

MPC

0.0037

ClinPred

0.0020

GERP RS

2.5

gMVP

0.17

Mutation Taster

=75/25

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over