16-1211987-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_021098.3(CACNA1H):c.4608C>A(p.Ile1536Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I1536I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.18

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: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.26).

BP7

Synonymous conserved (PhyloP=1.18 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4608C>A	p.Ile1536Ile	synonymous_variant	Exon 25 of 35	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000348261.11 link	c.4608C>A	p.Ile1536Ile	synonymous_variant	Exon 25 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4608C>A	p.Ile1536Ile	synonymous_variant	Exon 25 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4644C>A	p.Ile1548Ile	synonymous_variant	Exon 25 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4608C>A	p.Ile1536Ile	synonymous_variant	Exon 25 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000564231.6 link	c.4608C>A	p.Ile1536Ile	synonymous_variant	Exon 25 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4569C>A	p.Ile1523Ile	synonymous_variant	Exon 25 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4608C>A	p.Ile1536Ile	synonymous_variant	Exon 25 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4569C>A	p.Ile1523Ile	synonymous_variant	Exon 25 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4608C>A	p.Ile1536Ile	synonymous_variant	Exon 25 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4608C>A	p.Ile1536Ile	synonymous_variant	Exon 25 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4608C>A	p.Ile1536Ile	synonymous_variant	Exon 25 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4608C>A	p.Ile1536Ile	synonymous_variant	Exon 25 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4608C>A	p.Ile1536Ile	synonymous_variant	Exon 25 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4608C>A		non_coding_transcript_exon_variant	Exon 25 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*578C>A		non_coding_transcript_exon_variant	Exon 25 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000711448.1 link	n.4608C>A		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4608C>A		non_coding_transcript_exon_variant	Exon 25 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4608C>A		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4608C>A		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4608C>A		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4608C>A		non_coding_transcript_exon_variant	Exon 25 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4608C>A		non_coding_transcript_exon_variant	Exon 25 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4608C>A		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4608C>A		non_coding_transcript_exon_variant	Exon 25 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*578C>A		3_prime_UTR_variant	Exon 25 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000711450.1 link	c.4567-21C>A		intron_variant	Intron 24 of 34			ENSP00000518762.1
CACNA1H	ENST00000639478.1 link	n.4567-21C>A		intron_variant	Intron 24 of 34	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2480-21C>A		intron_variant	Intron 24 of 34	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4014-21C>A		intron_variant	Intron 23 of 33			ENSP00000518758.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461192

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726900

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111666

Other (OTH)

AF:

0.00

AC:

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Mar 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 1536 of the CACNA1H mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CACNA1H protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

1.2

Splicing

Name

Calibrated prediction

Score

Prediction

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

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over