16-1200711-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021098.3(CACNA1H):c.1120-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,565,512 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 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, intron

Scores

Splicing: ADA: 0.001939

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.392

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:

LOC124903623 (HGNC:):

LOC124903623 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 16-1200711-C-G is Benign according to our data. Variant chr16-1200711-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 529663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000204 (31/152326) while in subpopulation AMR AF = 0.00105 (16/15306). AF 95% confidence interval is 0.000655. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.1120-5C>G		splice_region_variant, intron_variant	Intron 7 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.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 34	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 33	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 34	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.1081-5C>G	splice_region_variant, intron_variant	Intron 7 of 34	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 33	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.1081-5C>G	splice_region_variant, intron_variant	Intron 7 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 33	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 34	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 34	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*567-5C>G	splice_region_variant, intron_variant	Intron 6 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.1120-5C>G	splice_region_variant, intron_variant	Intron 7 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000166

AC:

AN:

175096

AF XY:

0.000191

show subpopulations

Gnomad AFR exome

AF:

0.000107

Gnomad AMR exome

AF:

0.000191

Gnomad ASJ exome

AF:

0.000800

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000181

Gnomad OTH exome

AF:

0.000418

GnomAD4 exome

AF:

0.0000969

AC:

137

AN:

1413186

Hom.:

Cov.:

AF XY:

0.0000930

AC XY:

AN XY:

698766

show subpopulations

African (AFR)

AF:

0.0000936

AC:

AN:

32040

American (AMR)

AF:

0.000296

AC:

AN:

37222

Ashkenazi Jewish (ASJ)

AF:

0.000711

AC:

AN:

25330

East Asian (EAS)

AF:

0.00

AC:

AN:

36634

South Asian (SAS)

AF:

0.0000369

AC:

AN:

81204

European-Finnish (FIN)

AF:

0.0000405

AC:

AN:

49378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5550

European-Non Finnish (NFE)

AF:

0.0000809

AC:

AN:

1087230

Other (OTH)

AF:

0.000205

AC:

AN:

58598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.000204

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41572

American (AMR)

AF:

0.00105

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68018

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.0000855

Hom.:

Bravo

AF:

0.000242

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CACNA1H-related disorder

Benign:1

Feb 27, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.38

(source)

DANN

Benign

0.27

PhyloP100

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0019

dbscSNV1_RF

Benign

0.054

SpliceAI score (max)

0.020

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