16-1211475-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The ENST00000711493.1(CACNA1H):c.4381C>T(p.Arg1461Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,612,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/7 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1461H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CACNA1H
ENST00000711493.1 missense

Scores

Splicing: ADA: 0.00002256

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.164

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 16-1211475-C-T is Benign according to our data. Variant chr16-1211475-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 529676.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 34	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000711493.1 link	c.4381C>T	p.Arg1461Cys	missense_variant	Exon 23 of 34			ENSP00000518778.1
CACNA1H	ENST00000348261.11 link	c.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 34	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 33	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000565831.7 link	c.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 34	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4312-6C>T		splice_region_variant, intron_variant	Intron 22 of 34	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 33	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4312-6C>T		splice_region_variant, intron_variant	Intron 22 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*321-6C>T		splice_region_variant, intron_variant	Intron 22 of 33	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 34	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2264-6C>T		splice_region_variant, intron_variant	Intron 22 of 34	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3798-6C>T		splice_region_variant, intron_variant	Intron 21 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4351-6C>T		splice_region_variant, intron_variant	Intron 22 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000162

AC:

AN:

247386

AF XY:

0.0000223

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1460100

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726354

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33466

American (AMR)

AF:

0.0000224

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000900

AC:

AN:

1111660

Other (OTH)

AF:

0.0000332

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000491

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Oct 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

3.7

(source)

DANN

Benign

0.59

PhyloP100

-0.16

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000023

dbscSNV1_RF

Benign

0.012

SpliceAI score (max)

0.070

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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16-1211475-C-T

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