16-1213775-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000711450.1(CACNA1H):c.4788C>T(p.Pro1596Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,547,640 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 1 hom. )

Consequence

CACNA1H
ENST00000711450.1 synonymous

Scores

Splicing: ADA: 0.00002190

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.22

Publications

2 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 -21 ACMG points.

BP4

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

BP6

Variant 16-1213775-C-T is Benign according to our data. Variant chr16-1213775-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.22 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00125 (190/152048) while in subpopulation AMR AF = 0.00274 (42/15308). AF 95% confidence interval is 0.00209. There are 1 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 190 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4778-5C>T		splice_region_variant, intron_variant	Intron 26 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000711450.1 link	c.4788C>T	p.Pro1596Pro	synonymous_variant	Exon 27 of 35			ENSP00000518762.1
CACNA1H	ENST00000711442.1 link	n.*4217C>T		non_coding_transcript_exon_variant	Exon 25 of 34			ENSP00000518758.1
CACNA1H	ENST00000711451.1 link	n.4850C>T		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518763.1
CACNA1H	ENST00000711488.1 link	n.4832C>T		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*4217C>T		3_prime_UTR_variant	Exon 25 of 34			ENSP00000518758.1
CACNA1H	ENST00000348261.11 link	c.4778-5C>T		splice_region_variant, intron_variant	Intron 26 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.4793-5C>T		splice_region_variant, intron_variant	Intron 25 of 33	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.4796-5C>T		splice_region_variant, intron_variant	Intron 25 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4760-5C>T		splice_region_variant, intron_variant	Intron 25 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000564231.6 link	c.4778-5C>T		splice_region_variant, intron_variant	Intron 26 of 34	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.4739-5C>T		splice_region_variant, intron_variant	Intron 26 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.4760-5C>T		splice_region_variant, intron_variant	Intron 25 of 33	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.4721-5C>T		splice_region_variant, intron_variant	Intron 25 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4778-5C>T		splice_region_variant, intron_variant	Intron 26 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4760-5C>T		splice_region_variant, intron_variant	Intron 25 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4778-5C>T		splice_region_variant, intron_variant	Intron 26 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4778-5C>T		splice_region_variant, intron_variant	Intron 26 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4778-5C>T		splice_region_variant, intron_variant	Intron 26 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4778-5C>T		splice_region_variant, intron_variant	Intron 26 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*730-5C>T		splice_region_variant, intron_variant	Intron 25 of 33	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.4716-5C>T		splice_region_variant, intron_variant	Intron 26 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*2629-5C>T		splice_region_variant, intron_variant	Intron 26 of 34	5		ENSP00000491488.1
CACNA1H	ENST00000711448.1 link	n.4760-5C>T		splice_region_variant, intron_variant	Intron 25 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4760-5C>T		splice_region_variant, intron_variant	Intron 25 of 34			ENSP00000518761.1
CACNA1H	ENST00000711452.1 link	n.4778-5C>T		splice_region_variant, intron_variant	Intron 26 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4778-5C>T		splice_region_variant, intron_variant	Intron 26 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4760-5C>T		splice_region_variant, intron_variant	Intron 25 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4778-5C>T		splice_region_variant, intron_variant	Intron 26 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4778-5C>T		splice_region_variant, intron_variant	Intron 26 of 35			ENSP00000518776.1

Frequencies

GnomAD3 genomes

AF:

0.00125

AC:

190

AN:

151930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000556

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00149

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00143

AC:

223

AN:

155958

AF XY:

0.00133

show subpopulations

Gnomad AFR exome

AF:

0.000237

Gnomad AMR exome

AF:

0.00184

Gnomad ASJ exome

AF:

0.00726

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000884

Gnomad NFE exome

AF:

0.00158

Gnomad OTH exome

AF:

0.00268

GnomAD4 exome

AF:

0.00133

AC:

1852

AN:

1395592

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

897

AN XY:

688868

show subpopulations

African (AFR)

AF:

0.000220

AC:

AN:

31790

American (AMR)

AF:

0.00217

AC:

AN:

35968

Ashkenazi Jewish (ASJ)

AF:

0.00635

AC:

160

AN:

25182

East Asian (EAS)

AF:

0.0000552

AC:

AN:

36242

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79674

European-Finnish (FIN)

AF:

0.0000473

AC:

AN:

42312

Middle Eastern (MID)

AF:

0.000180

AC:

AN:

5548

European-Non Finnish (NFE)

AF:

0.00140

AC:

1514

AN:

1080800

Other (OTH)

AF:

0.00150

AC:

AN:

58076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

189

283

378

472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

124

186

248

310

<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:

0.00125

AC:

190

AN:

152048

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.000554

AC:

AN:

41524

American (AMR)

AF:

0.00274

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5110

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00149

AC:

101

AN:

67894

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.00175

Hom.:

Bravo

AF:

0.00156

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Apr 11, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BS1, BS2 -

Jun 17, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

CACNA1H-related disorder

Benign:1

Mar 30, 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 22, 2025

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

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.77

(source)

DANN

Benign

0.95

PhyloP100

-2.2

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000022

dbscSNV1_RF

Benign

0.0020

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