NM_021098.3:c.6013C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021098.3(CACNA1H):c.6013C>T(p.Arg2005Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0595 in 1,547,162 control chromosomes in the GnomAD database, including 3,216 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2005S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.047 ( 245 hom., cov: 33)

Exomes 𝑓: 0.061 ( 2971 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.198

Publications

14 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 (MetaRNN=0.0018978119).

BP6

Variant 16-1219095-C-T is Benign according to our data. Variant chr16-1219095-C-T is described in ClinVar as Benign. ClinVar VariationId is 585654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.6013C>T	p.Arg2005Cys	missense_variant	Exon 34 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.6013C>T	p.Arg2005Cys	missense_variant	Exon 34 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.6028C>T	p.Arg2010Cys	missense_variant	Exon 33 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.5998C>T	p.Arg2000Cys	missense_variant	Exon 33 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5995C>T	p.Arg1999Cys	missense_variant	Exon 33 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.5995C>T	p.Arg1999Cys	missense_variant	Exon 34 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5980C>T	p.Arg1994Cys	missense_variant	Exon 34 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.5974C>T	p.Arg1992Cys	missense_variant	Exon 34 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.5962C>T	p.Arg1988Cys	missense_variant	Exon 33 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.5956C>T	p.Arg1986Cys	missense_variant	Exon 33 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.6013C>T	p.Arg2005Cys	missense_variant	Exon 34 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5962C>T	p.Arg1988Cys	missense_variant	Exon 33 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5935C>T	p.Arg1979Cys	missense_variant	Exon 34 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.6013C>T	p.Arg2005Cys	missense_variant	Exon 34 of 35			ENSP00000518772.1
CACNA1H	ENST00000621827.2 link	n.6013C>T		non_coding_transcript_exon_variant	Exon 34 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1932C>T		non_coding_transcript_exon_variant	Exon 33 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*1061C>T		non_coding_transcript_exon_variant	Exon 34 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3831C>T		non_coding_transcript_exon_variant	Exon 34 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*5457C>T		non_coding_transcript_exon_variant	Exon 32 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*954C>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*872C>T		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1592C>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*680C>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*647C>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5962C>T		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.6013C>T		non_coding_transcript_exon_variant	Exon 34 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5980C>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*1129C>T		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*1932C>T		3_prime_UTR_variant	Exon 33 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*1061C>T		3_prime_UTR_variant	Exon 34 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3831C>T		3_prime_UTR_variant	Exon 34 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*5457C>T		3_prime_UTR_variant	Exon 32 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*954C>T		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*872C>T		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1592C>T		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*680C>T		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*647C>T		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518765.1
CACNA1H	ENST00000711488.1 link	n.*1129C>T		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518777.1
CACNA1H	ENST00000711456.1 link	c.5887+444C>T		intron_variant	Intron 33 of 33			ENSP00000518769.1

Frequencies

GnomAD3 genomes

AF:

0.0470

AC:

7149

AN:

152178

Hom.:

244

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00944

Gnomad AMI

AF:

0.169

Gnomad AMR

AF:

0.0436

Gnomad ASJ

AF:

0.0910

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0787

Gnomad FIN

AF:

0.0490

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0672

Gnomad OTH

AF:

0.0578

GnomAD2 exomes

AF:

0.0566

AC:

8457

AN:

149494

AF XY:

0.0607

show subpopulations

Gnomad AFR exome

AF:

0.00750

Gnomad AMR exome

AF:

0.0330

Gnomad ASJ exome

AF:

0.0954

Gnomad EAS exome

AF:

0.000186

Gnomad FIN exome

AF:

0.0498

Gnomad NFE exome

AF:

0.0664

Gnomad OTH exome

AF:

0.0695

GnomAD4 exome

AF:

0.0609

AC:

84965

AN:

1394866

Hom.:

2971

Cov.:

AF XY:

0.0620

AC XY:

42610

AN XY:

687636

show subpopulations

African (AFR)

AF:

0.00831

AC:

262

AN:

31546

American (AMR)

AF:

0.0339

AC:

1205

AN:

35558

Ashkenazi Jewish (ASJ)

AF:

0.0944

AC:

2366

AN:

25066

East Asian (EAS)

AF:

0.000196

AC:

AN:

35648

South Asian (SAS)

AF:

0.0851

AC:

6725

AN:

79062

European-Finnish (FIN)

AF:

0.0513

AC:

2424

AN:

47280

Middle Eastern (MID)

AF:

0.0835

AC:

474

AN:

5678

European-Non Finnish (NFE)

AF:

0.0631

AC:

67983

AN:

1077204

Other (OTH)

AF:

0.0609

AC:

3519

AN:

57824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

3889

7778

11666

15555

19444

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2462

4924

7386

9848

12310

<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:

0.0470

AC:

7151

AN:

152296

Hom.:

245

Cov.:

AF XY:

0.0455

AC XY:

3391

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00941

AC:

391

AN:

41552

American (AMR)

AF:

0.0436

AC:

667

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0910

AC:

316

AN:

3472

East Asian (EAS)

AF:

0.00135

AC:

AN:

5184

South Asian (SAS)

AF:

0.0794

AC:

383

AN:

4824

European-Finnish (FIN)

AF:

0.0490

AC:

520

AN:

10622

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0672

AC:

4570

AN:

68012

Other (OTH)

AF:

0.0568

AC:

120

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

347

694

1041

1388

1735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<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:

0.0594

Hom.:

323

Bravo

AF:

0.0420

TwinsUK

AF:

0.0618

AC:

229

ALSPAC

AF:

0.0579

AC:

223

ESP6500AA

AF:

0.00739

AC:

ESP6500EA

AF:

0.0536

AC:

389

ExAC

AF:

0.0289

AC:

2059

Asia WGS

AF:

0.0310

AC:

108

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 07, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17696120, 28933792, 29588962) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 20, 2017

Athena Diagnostics

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

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

8.9

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.51

D;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.72

T;T;T;.

MetaRNN

Benign

0.0019

T;T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.9

L;.;.;.

PhyloP100

0.20

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.9

D;.;D;D

REVEL

Benign

0.26

Sift

Benign

0.052

T;.;T;T

Sift4G

Uncertain

0.043

D;.;D;D

Polyphen

0.0010

B;.;B;B

Vest4

0.12

ClinPred

0.029

GERP RS

-1.9

Varity_R

0.17

gMVP

0.31

Mutation Taster

=97/3

polymorphism (auto)

(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