NM_021098.3:c.412-5C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_021098.3(CACNA1H):c.412-5C>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 0.0000122 in 1,551,660 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000086 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, intron

Scores

Splicing: ADA: 0.00003284

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.41

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000046 (7/152192) while in subpopulation EAS AF = 0.000969 (5/5160). AF 95% confidence interval is 0.000381. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.412-5C>T		splice_region_variant, intron_variant	Intron 3 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 33	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 34	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.412-44C>T	intron_variant	Intron 3 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 33	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.412-44C>T	intron_variant	Intron 3 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 33	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 34	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.412-5C>T	splice_region_variant, intron_variant	Intron 3 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000967

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

157272

AF XY:

0.0000241

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000274

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000164

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000857

AC:

AN:

1399468

Hom.:

Cov.:

AF XY:

0.00000579

AC XY:

AN XY:

690264

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31628

American (AMR)

AF:

0.0000280

AC:

AN:

35744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25172

East Asian (EAS)

AF:

0.0000559

AC:

AN:

35760

South Asian (SAS)

AF:

0.0000757

AC:

AN:

79220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5442

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1079162

Other (OTH)

AF:

0.00

AC:

AN:

58012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000460

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41538

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000969

AC:

AN:

5160

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67996

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.1

(source)

DANN

Benign

0.58

PhyloP100

-2.4

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000033

dbscSNV1_RF

Benign

0.0060

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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