16-1223982-C-T

Variant names:

Variant summary

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

The ENST00000621827.2(CACNA1H):n.*1122C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 227,830 control chromosomes in the GnomAD database, including 22,649 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.45 ( 15386 hom., cov: 27)

Exomes 𝑓: 0.39 ( 7263 hom. )

Consequence

CACNA1H
ENST00000621827.2 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.684

Publications

3 publications found

Variant links:

Genes affected

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 links:

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:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPSG1	NM_012467.4 link	c.74-388G>A		intron_variant	Intron 2 of 5	ENST00000234798.5	NP_036599.4	Q9NRR2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000621827.2 link	n.*1122C>T	non_coding_transcript_exon_variant	Exon 37 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000711486.1 link	n.*2451C>T	non_coding_transcript_exon_variant	Exon 37 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.*2843C>T	non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518776.1
CACNA1H	ENST00000564231.6 link	c.*2988C>T	3_prime_UTR_variant	Exon 35 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000711438.1 link	c.*2988C>T	3_prime_UTR_variant	Exon 34 of 34			ENSP00000518754.1
CACNA1H	ENST00000621827.2 link	n.*1122C>T	3_prime_UTR_variant	Exon 37 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000711486.1 link	n.*2451C>T	3_prime_UTR_variant	Exon 37 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.*2843C>T	3_prime_UTR_variant	Exon 36 of 36			ENSP00000518776.1
TPSG1	ENST00000234798.5 link	c.74-388G>A	intron_variant	Intron 2 of 5	1	NM_012467.4	ENSP00000234798.4	Q9NRR2

Frequencies

GnomAD3 genomes

AF:

0.448

AC:

66847

AN:

149186

Hom.:

15398

Cov.:

show subpopulations

Gnomad AFR

AF:

0.371

Gnomad AMI

AF:

0.370

Gnomad AMR

AF:

0.437

Gnomad ASJ

AF:

0.469

Gnomad EAS

AF:

0.750

Gnomad SAS

AF:

0.432

Gnomad FIN

AF:

0.600

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.452

Gnomad OTH

AF:

0.455

GnomAD4 exome

AF:

0.391

AC:

30676

AN:

78534

Hom.:

7263

Cov.:

AF XY:

0.386

AC XY:

15404

AN XY:

39864

show subpopulations

African (AFR)

AF:

0.249

AC:

419

AN:

1682

American (AMR)

AF:

0.322

AC:

641

AN:

1992

Ashkenazi Jewish (ASJ)

AF:

0.360

AC:

875

AN:

2432

East Asian (EAS)

AF:

0.742

AC:

1347

AN:

1816

South Asian (SAS)

AF:

0.371

AC:

2861

AN:

7708

European-Finnish (FIN)

AF:

0.517

AC:

2443

AN:

4728

Middle Eastern (MID)

AF:

0.312

AC:

124

AN:

398

European-Non Finnish (NFE)

AF:

0.380

AC:

20044

AN:

52762

Other (OTH)

AF:

0.383

AC:

1922

AN:

5016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

797

1595

2392

3190

3987

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.448

AC:

66859

AN:

149296

Hom.:

15386

Cov.:

AF XY:

0.454

AC XY:

33052

AN XY:

72780

show subpopulations

African (AFR)

AF:

0.371

AC:

14862

AN:

40096

American (AMR)

AF:

0.437

AC:

6578

AN:

15048

Ashkenazi Jewish (ASJ)

AF:

0.469

AC:

1620

AN:

3454

East Asian (EAS)

AF:

0.750

AC:

3760

AN:

5012

South Asian (SAS)

AF:

0.432

AC:

2035

AN:

4710

European-Finnish (FIN)

AF:

0.600

AC:

6129

AN:

10218

Middle Eastern (MID)

AF:

0.422

AC:

124

AN:

294

European-Non Finnish (NFE)

AF:

0.452

AC:

30482

AN:

67498

Other (OTH)

AF:

0.453

AC:

934

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1783

3566

5350

7133

8916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.427

Hom.:

2510

Bravo

AF:

0.432

Asia WGS

AF:

0.516

AC:

1791

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.98

(source)

DANN

Benign

0.69

PhyloP100

-0.68

Mutation Taster

=100/0

polymorphism (auto)

(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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16-1223982-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over