NM_021098.3:c.4558G>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -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 (★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -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	ENST00000565831.6 link	c.4558G>A	p.Asp1520Asn	missense_variant	Exon 23 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 link	c.4519G>A	p.Asp1507Asn	missense_variant	Exon 24 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000569107.5 link	c.781G>A	p.Asp261Asn	missense_variant	Exon 7 of 17	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000564231.5 link	c.781G>A	p.Asp261Asn	missense_variant	Exon 7 of 18	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000562079.5 link	c.781G>A	p.Asp261Asn	missense_variant	Exon 7 of 17	1		ENSP00000454581.2	H3BMW6
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	ENST00000640028.1 link	n.*2471G>A		3_prime_UTR_variant	Exon 24 of 35	5		ENSP00000491488.1	A0A1W2PQ19

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

GnomAD3 exomes

AF:

0.0000524

AC:

AN:

247982

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134806

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over