NM_021098.3:c.1120-3dupC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PVS1_ModerateBP6_ModerateBS2

The NM_021098.3(CACNA1H):c.1120-3dupC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,564,964 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.255

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: Likely_benign. The variant received -4 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0131690735 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.2, offset of 0 (no position change), new splice context is: caagccactgccccccccAGgtg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant 16-1200706-G-GC is Benign according to our data. Variant chr16-1200706-G-GC is described in ClinVar as [Benign]. Clinvar id is 1165632.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.1120-3dupC		splice_acceptor_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.1120-10_1120-9insC	intron_variant	Intron 7 of 34	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.1120-10_1120-9insC	intron_variant	Intron 7 of 33	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.1120-10_1120-9insC	intron_variant	Intron 7 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.1120-10_1120-9insC	intron_variant	Intron 7 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.1120-10_1120-9insC	intron_variant	Intron 7 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.1120-10_1120-9insC	intron_variant	Intron 7 of 34	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.1081-10_1081-9insC	intron_variant	Intron 7 of 34	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.1120-10_1120-9insC	intron_variant	Intron 7 of 33	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.1081-10_1081-9insC	intron_variant	Intron 7 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.1120-10_1120-9insC	intron_variant	Intron 7 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.1120-10_1120-9insC	intron_variant	Intron 7 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.1120-10_1120-9insC	intron_variant	Intron 7 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.1120-10_1120-9insC	intron_variant	Intron 7 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.1120-10_1120-9insC	intron_variant	Intron 7 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.1120-10_1120-9insC	intron_variant	Intron 7 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.1120-10_1120-9insC	intron_variant	Intron 7 of 33	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.1120-10_1120-9insC	intron_variant	Intron 7 of 34	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.1120-10_1120-9insC	intron_variant	Intron 7 of 34	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.567-10_567-9insC	intron_variant	Intron 6 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.1120-10_1120-9insC	intron_variant	Intron 7 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.1120-10_1120-9insC	intron_variant	Intron 7 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.1120-10_1120-9insC	intron_variant	Intron 7 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.1120-10_1120-9insC	intron_variant	Intron 7 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.1120-10_1120-9insC	intron_variant	Intron 7 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.1120-10_1120-9insC	intron_variant	Intron 7 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.1120-10_1120-9insC	intron_variant	Intron 7 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.1120-10_1120-9insC	intron_variant	Intron 7 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.1120-10_1120-9insC	intron_variant	Intron 7 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000749

AC:

AN:

173676

AF XY:

0.0000429

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000383

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000591

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000210

GnomAD4 exome

AF:

0.0000623

AC:

AN:

1412814

Hom.:

Cov.:

AF XY:

0.0000558

AC XY:

AN XY:

698642

show subpopulations

African (AFR)

AF:

0.0000624

AC:

AN:

32052

American (AMR)

AF:

0.000322

AC:

AN:

37258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25334

East Asian (EAS)

AF:

0.00

AC:

AN:

36620

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81308

European-Finnish (FIN)

AF:

0.000203

AC:

AN:

49242

Middle Eastern (MID)

AF:

0.000182

AC:

AN:

5508

European-Non Finnish (NFE)

AF:

0.0000534

AC:

AN:

1086910

Other (OTH)

AF:

0.0000683

AC:

AN:

58582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

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:

0.0000526

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

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:

0.0000945

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CACNA1H-related disorder

Benign:1

Jul 25, 2021

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 01, 2024

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

PhyloP100

0.26

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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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