16-1213939-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_021098.3(CACNA1H):c.4929+8C>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 0.000128 in 1,607,200 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (no stars).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, intron

Scores

Splicing: ADA: 0.00006484

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.724

Publications

4 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 16-1213939-C-G is Benign according to our data. Variant chr16-1213939-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3042066.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4929+8C>G		splice_region_variant, intron_variant	Intron 27 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.4929+8C>G	splice_region_variant, intron_variant	Intron 27 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.4944+8C>G	splice_region_variant, intron_variant	Intron 26 of 33	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.4947+8C>G	splice_region_variant, intron_variant	Intron 26 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4911+8C>G	splice_region_variant, intron_variant	Intron 26 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.4944+8C>G	splice_region_variant, intron_variant	Intron 27 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4929+8C>G	splice_region_variant, intron_variant	Intron 27 of 34	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.4890+8C>G	splice_region_variant, intron_variant	Intron 27 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.4911+8C>G	splice_region_variant, intron_variant	Intron 26 of 33	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.4872+8C>G	splice_region_variant, intron_variant	Intron 26 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4929+8C>G	splice_region_variant, intron_variant	Intron 27 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4911+8C>G	splice_region_variant, intron_variant	Intron 26 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4929+8C>G	splice_region_variant, intron_variant	Intron 27 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4929+8C>G	splice_region_variant, intron_variant	Intron 27 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4929+8C>G	splice_region_variant, intron_variant	Intron 27 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4929+8C>G	splice_region_variant, intron_variant	Intron 27 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*881+8C>G	splice_region_variant, intron_variant	Intron 26 of 33	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*10+8C>G	splice_region_variant, intron_variant	Intron 27 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*2780+8C>G	splice_region_variant, intron_variant	Intron 27 of 34	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*4373+8C>G	splice_region_variant, intron_variant	Intron 25 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4911+8C>G	splice_region_variant, intron_variant	Intron 26 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4911+8C>G	splice_region_variant, intron_variant	Intron 26 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.5006+8C>G	splice_region_variant, intron_variant	Intron 27 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4929+8C>G	splice_region_variant, intron_variant	Intron 27 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4929+8C>G	splice_region_variant, intron_variant	Intron 27 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4911+8C>G	splice_region_variant, intron_variant	Intron 26 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4929+8C>G	splice_region_variant, intron_variant	Intron 27 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4929+8C>G	splice_region_variant, intron_variant	Intron 27 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4988+8C>G	splice_region_variant, intron_variant	Intron 26 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000347

AC:

AN:

236234

AF XY:

0.000373

show subpopulations

Gnomad AFR exome

AF:

0.000504

Gnomad AMR exome

AF:

0.0000299

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00355

Gnomad NFE exome

AF:

0.00000935

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.000107

AC:

155

AN:

1454928

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

723126

show subpopulations

African (AFR)

AF:

0.000210

AC:

AN:

33404

American (AMR)

AF:

0.0000680

AC:

AN:

44110

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25968

East Asian (EAS)

AF:

0.00

AC:

AN:

39464

South Asian (SAS)

AF:

0.00

AC:

AN:

85004

European-Finnish (FIN)

AF:

0.00276

AC:

142

AN:

51470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109670

Other (OTH)

AF:

0.0000166

AC:

AN:

60084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000335

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41574

American (AMR)

AF:

0.0000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00376

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.00

Hom.:

Bravo

AF:

0.0000642

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CACNA1H-related disorder

Benign:1

May 09, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.43

(source)

DANN

Benign

0.32

PhyloP100

-0.72

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000065

dbscSNV1_RF

Benign

0.032

SpliceAI score (max)

0.010

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