ENST00000711482.1:c.6127C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000711482.1(CACNA1H):c.6127C>T(p.Arg2043Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,520,138 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 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. R2043G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0087 ( 10 hom., cov: 35)

Exomes 𝑓: 0.012 ( 126 hom. )

Consequence

CACNA1H
ENST00000711482.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.72

Publications

1 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 16-1220166-C-T is Benign according to our data. Variant chr16-1220166-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00869 (1323/152330) while in subpopulation NFE AF = 0.014 (949/68010). AF 95% confidence interval is 0.0132. There are 10 homozygotes in GnomAd4. There are 576 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High AC in GnomAd4 at 1323 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.6234C>T	p.Cys2078Cys	synonymous_variant	Exon 35 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000711482.1 link	c.6127C>T	p.Arg2043Cys	missense_variant	Exon 36 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.6076C>T	p.Arg2026Cys	missense_variant	Exon 35 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.6049C>T	p.Arg2017Cys	missense_variant	Exon 36 of 36			ENSP00000518768.1
CACNA1H	ENST00000348261.11 link	c.6234C>T	p.Cys2078Cys	synonymous_variant	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.6249C>T	p.Cys2083Cys	synonymous_variant	Exon 34 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.6219C>T	p.Cys2073Cys	synonymous_variant	Exon 34 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.6216C>T	p.Cys2072Cys	synonymous_variant	Exon 34 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.6216C>T	p.Cys2072Cys	synonymous_variant	Exon 35 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.6201C>T	p.Cys2067Cys	synonymous_variant	Exon 35 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.6195C>T	p.Cys2065Cys	synonymous_variant	Exon 35 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.6183C>T	p.Cys2061Cys	synonymous_variant	Exon 34 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.6177C>T	p.Cys2059Cys	synonymous_variant	Exon 34 of 34			ENSP00000518754.1
CACNA1H	ENST00000637236.3 link	n.*2153C>T		non_coding_transcript_exon_variant	Exon 34 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*1282C>T		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*4052C>T		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*5678C>T		non_coding_transcript_exon_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*1175C>T		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*1093C>T		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1813C>T		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*901C>T		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*868C>T		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.*148C>T		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.6234C>T		non_coding_transcript_exon_variant	Exon 35 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.6201C>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*1350C>T		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000711483.1 link	c.*148C>T		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.*148C>T		3_prime_UTR_variant	Exon 34 of 34			ENSP00000518769.1
CACNA1H	ENST00000637236.3 link	n.*2153C>T		3_prime_UTR_variant	Exon 34 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*1282C>T		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*4052C>T		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*5678C>T		3_prime_UTR_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*1175C>T		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*1093C>T		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1813C>T		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*901C>T		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*868C>T		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.*148C>T		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711488.1 link	n.*1350C>T		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000621827.2 link	n.6121+113C>T		intron_variant	Intron 35 of 36	6		ENSP00000518766.1

Frequencies

GnomAD3 genomes

AF:

0.00869

AC:

1323

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00265

Gnomad AMI

AF:

0.0275

Gnomad AMR

AF:

0.00876

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0140

Gnomad OTH

AF:

0.0162

GnomAD2 exomes

AF:

0.00947

AC:

1528

AN:

161270

AF XY:

0.00939

show subpopulations

Gnomad AFR exome

AF:

0.00270

Gnomad AMR exome

AF:

0.0101

Gnomad ASJ exome

AF:

0.0125

Gnomad EAS exome

AF:

0.000422

Gnomad FIN exome

AF:

0.00221

Gnomad NFE exome

AF:

0.0142

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.0119

AC:

16236

AN:

1367808

Hom.:

126

Cov.:

AF XY:

0.0115

AC XY:

7738

AN XY:

673204

show subpopulations

African (AFR)

AF:

0.00160

AC:

AN:

28070

American (AMR)

AF:

0.00970

AC:

312

AN:

32162

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

255

AN:

21028

East Asian (EAS)

AF:

0.000113

AC:

AN:

35528

South Asian (SAS)

AF:

0.00247

AC:

178

AN:

71974

European-Finnish (FIN)

AF:

0.00275

AC:

133

AN:

48282

Middle Eastern (MID)

AF:

0.0108

AC:

AN:

5362

European-Non Finnish (NFE)

AF:

0.0137

AC:

14677

AN:

1069114

Other (OTH)

AF:

0.0102

AC:

574

AN:

56288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

978

1957

2935

3914

4892

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

546

1092

1638

2184

2730

<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:

0.00869

AC:

1323

AN:

152330

Hom.:

Cov.:

AF XY:

0.00773

AC XY:

576

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00265

AC:

110

AN:

41584

American (AMR)

AF:

0.00875

AC:

134

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.00145

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0140

AC:

949

AN:

68010

Other (OTH)

AF:

0.0161

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

136

203

271

339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00780

Hom.:

Bravo

AF:

0.00889

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 25, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BS1, BS2 -

not specified

Benign:2

Jul 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 03, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 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

-0.69

CADD

Benign

2.0

(source)

DANN

Benign

0.90

PhyloP100

-1.7

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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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