rs555853603

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_021098.3(CACNA1H):c.4558G>A(p.Asp1520Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000285 in 1,612,536 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1520G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.45

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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4558G>A	p.Asp1520Asn	missense_variant	Exon 24 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.4558G>A	p.Asp1520Asn	missense_variant	Exon 24 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4558G>A	p.Asp1520Asn	missense_variant	Exon 24 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4594G>A	p.Asp1532Asn	missense_variant	Exon 24 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4558G>A	p.Asp1520Asn	missense_variant	Exon 24 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4558G>A	p.Asp1520Asn	missense_variant	Exon 24 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4558G>A	p.Asp1520Asn	missense_variant	Exon 24 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4519G>A	p.Asp1507Asn	missense_variant	Exon 24 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4558G>A	p.Asp1520Asn	missense_variant	Exon 24 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4519G>A	p.Asp1507Asn	missense_variant	Exon 24 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4558G>A	p.Asp1520Asn	missense_variant	Exon 24 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4558G>A	p.Asp1520Asn	missense_variant	Exon 24 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4558G>A	p.Asp1520Asn	missense_variant	Exon 24 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4558G>A	p.Asp1520Asn	missense_variant	Exon 24 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4558G>A	p.Asp1520Asn	missense_variant	Exon 24 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4558G>A		non_coding_transcript_exon_variant	Exon 24 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*528G>A		non_coding_transcript_exon_variant	Exon 24 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4558G>A		non_coding_transcript_exon_variant	Exon 24 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2471G>A		non_coding_transcript_exon_variant	Exon 24 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4005G>A		non_coding_transcript_exon_variant	Exon 23 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4558G>A		non_coding_transcript_exon_variant	Exon 24 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4558G>A		non_coding_transcript_exon_variant	Exon 24 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4558G>A		non_coding_transcript_exon_variant	Exon 24 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4558G>A		non_coding_transcript_exon_variant	Exon 24 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4558G>A		non_coding_transcript_exon_variant	Exon 24 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4558G>A		non_coding_transcript_exon_variant	Exon 24 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4558G>A		non_coding_transcript_exon_variant	Exon 24 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4558G>A		non_coding_transcript_exon_variant	Exon 24 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4558G>A		non_coding_transcript_exon_variant	Exon 24 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*528G>A		3_prime_UTR_variant	Exon 24 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2471G>A		3_prime_UTR_variant	Exon 24 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4005G>A		3_prime_UTR_variant	Exon 23 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000524

AC:

AN:

247982

AF XY:

0.0000223

show subpopulations

Gnomad AFR exome

AF:

0.0000651

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1460184

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726372

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33468

American (AMR)

AF:

0.000157

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1111662

Other (OTH)

AF:

0.0000663

AC:

AN:

60338

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

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41574

American (AMR)

AF:

0.000196

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2116

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:

0.0000678

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000496

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Jul 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1520 of the CACNA1H protein (p.Asp1520Asn). This variant is present in population databases (rs555853603, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. ClinVar contains an entry for this variant (Variation ID: 460119). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1H protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;.;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

D;D;D;.

M_CAP

Pathogenic

0.72

MetaRNN

Uncertain

0.66

D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.4

M;.;M;M

PhyloP100

6.4

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.8

D;.;D;D

REVEL

Uncertain

0.54

Sift

Benign

0.053

T;.;T;T

Sift4G

Uncertain

0.026

D;.;D;D

Polyphen

1.0

D;.;P;P

Vest4

0.40

MVP

0.93

ClinPred

0.68

GERP RS

3.5

Varity_R

0.36

gMVP

0.72

Mutation Taster

=70/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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