NM_021098.3:c.2030C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_021098.3(CACNA1H):c.2030C>T(p.Ser677Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000351 in 1,570,902 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. S677S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00069 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00031 ( 2 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 7.19

Publications

3 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00918287).

BP6

Variant 16-1204037-C-T is Benign according to our data. Variant chr16-1204037-C-T is described in ClinVar as [Benign]. Clinvar id is 460058.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000689 (105/152336) while in subpopulation EAS AF = 0.0163 (84/5168). AF 95% confidence interval is 0.0135. There are 1 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 105 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.2030C>T	p.Ser677Leu	missense_variant	Exon 10 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.2030C>T	p.Ser677Leu	missense_variant	Exon 10 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.2030C>T	p.Ser677Leu	missense_variant	Exon 10 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.2030C>T	p.Ser677Leu	missense_variant	Exon 10 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.2030C>T	p.Ser677Leu	missense_variant	Exon 10 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.2030C>T	p.Ser677Leu	missense_variant	Exon 10 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.2030C>T	p.Ser677Leu	missense_variant	Exon 10 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.1991C>T	p.Ser664Leu	missense_variant	Exon 10 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.2030C>T	p.Ser677Leu	missense_variant	Exon 10 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.1991C>T	p.Ser664Leu	missense_variant	Exon 10 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.2030C>T	p.Ser677Leu	missense_variant	Exon 10 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.2030C>T	p.Ser677Leu	missense_variant	Exon 10 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.2030C>T	p.Ser677Leu	missense_variant	Exon 10 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.2030C>T	p.Ser677Leu	missense_variant	Exon 10 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.2030C>T	p.Ser677Leu	missense_variant	Exon 10 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.2030C>T		non_coding_transcript_exon_variant	Exon 10 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.2030C>T		non_coding_transcript_exon_variant	Exon 10 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.2030C>T		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.1413C>T		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*1477C>T		non_coding_transcript_exon_variant	Exon 9 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.2030C>T		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.2030C>T		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.2030C>T		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.2030C>T		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.2030C>T		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.2030C>T		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.2030C>T		non_coding_transcript_exon_variant	Exon 10 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.2030C>T		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.2030C>T		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*1477C>T		3_prime_UTR_variant	Exon 9 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000683

AC:

104

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0162

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00119

AC:

217

AN:

181732

AF XY:

0.00111

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000140

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0148

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000523

Gnomad OTH exome

AF:

0.000412

GnomAD4 exome

AF:

0.000314

AC:

446

AN:

1418566

Hom.:

Cov.:

AF XY:

0.000319

AC XY:

224

AN XY:

701814

show subpopulations

African (AFR)

AF:

0.000277

AC:

AN:

32444

American (AMR)

AF:

0.000101

AC:

AN:

39524

Ashkenazi Jewish (ASJ)

AF:

0.0000394

AC:

AN:

25378

East Asian (EAS)

AF:

0.00912

AC:

340

AN:

37300

South Asian (SAS)

AF:

0.000382

AC:

AN:

81256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.0000192

AC:

AN:

1090942

Other (OTH)

AF:

0.000680

AC:

AN:

58794

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000689

AC:

105

AN:

152336

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41584

American (AMR)

AF:

0.000261

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0163

AC:

AN:

5168

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.0000896

Hom.:

Bravo

AF:

0.000669

ESP6500AA

AF:

0.000269

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000965

AC:

114

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CACNA1H-related disorder

Benign:1

Aug 09, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

Dec 22, 2024

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

0.18

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;.;.;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D;D;.

MetaRNN

Benign

0.0092

T;T;T;T

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.7

M;.;M;M

PhyloP100

7.2

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.1

N;.;N;N

REVEL

Uncertain

0.54

Sift

Benign

0.10

T;.;T;T

Sift4G

Benign

0.30

T;.;T;T

Polyphen

0.99

D;.;P;P

Vest4

0.50

MVP

0.95

ClinPred

0.068

GERP RS

4.3

Varity_R

0.28

gMVP

0.49

Mutation Taster

=52/48

polymorphism

(source)

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

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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