chr16-1206099-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_021098.3(CACNA1H):c.2604-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,566,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, intron

Scores

Splicing: ADA: 0.00002266

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.119

Publications

0 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 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 16-1206099-C-T is Benign according to our data. Variant chr16-1206099-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 585635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.2604-5C>T		splice_region_variant, intron_variant	Intron 11 of 34	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000348261.11 link	c.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 34	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 33	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 34	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.2565-5C>T	splice_region_variant, intron_variant	Intron 11 of 34	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 33	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.2565-5C>T	splice_region_variant, intron_variant	Intron 11 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 33	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 34	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*517-5C>T	splice_region_variant, intron_variant	Intron 11 of 34	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2051-5C>T	splice_region_variant, intron_variant	Intron 10 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.2604-5C>T	splice_region_variant, intron_variant	Intron 11 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000248

AC:

AN:

185538

AF XY:

0.000248

show subpopulations

Gnomad AFR exome

AF:

0.000191

Gnomad AMR exome

AF:

0.000275

Gnomad ASJ exome

AF:

0.000787

Gnomad EAS exome

AF:

0.000143

Gnomad FIN exome

AF:

0.000608

Gnomad NFE exome

AF:

0.000174

Gnomad OTH exome

AF:

0.00101

GnomAD4 exome

AF:

0.000190

AC:

269

AN:

1414072

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

132

AN XY:

699580

show subpopulations

African (AFR)

AF:

0.0000921

AC:

AN:

32568

American (AMR)

AF:

0.000300

AC:

AN:

39950

Ashkenazi Jewish (ASJ)

AF:

0.000711

AC:

AN:

25332

East Asian (EAS)

AF:

0.0000534

AC:

AN:

37446

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80536

European-Finnish (FIN)

AF:

0.000689

AC:

AN:

43526

Middle Eastern (MID)

AF:

0.000389

AC:

AN:

5142

European-Non Finnish (NFE)

AF:

0.000167

AC:

182

AN:

1090894

Other (OTH)

AF:

0.000324

AC:

AN:

58678

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000171

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41570

American (AMR)

AF:

0.000392

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68020

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000247

Hom.:

Bravo

AF:

0.000136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 21, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BP4 -

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV

Benign:1

Apr 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.0

(source)

DANN

Benign

0.76

PhyloP100

-0.12

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000023

dbscSNV1_RF

Benign

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over