NM_021098.3:c.4063G>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_021098.3(CACNA1H):c.4063G>A(p.Gly1355Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,602,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.53

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 -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.869

BS2

High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4063G>A	p.Gly1355Ser	missense_variant	Exon 21 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.4063G>A	p.Gly1355Ser	missense_variant	Exon 21 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 link	c.4063G>A	p.Gly1355Ser	missense_variant	Exon 20 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 link	c.4024G>A	p.Gly1342Ser	missense_variant	Exon 21 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000569107.5 link	c.286G>A	p.Gly96Ser	missense_variant	Exon 4 of 17	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000564231.5 link	c.286G>A	p.Gly96Ser	missense_variant	Exon 4 of 18	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000562079.5 link	c.286G>A	p.Gly96Ser	missense_variant	Exon 4 of 17	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000637236.2 link	n.*33G>A		non_coding_transcript_exon_variant	Exon 5 of 6	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4063G>A		non_coding_transcript_exon_variant	Exon 21 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1976G>A		non_coding_transcript_exon_variant	Exon 21 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000637236.2 link	n.*33G>A		3_prime_UTR_variant	Exon 5 of 6	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*1976G>A		3_prime_UTR_variant	Exon 21 of 35	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000292

AC:

AN:

239554

Hom.:

AF XY:

0.0000381

AC XY:

AN XY:

131280

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000901

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000200

AC:

AN:

1449986

Hom.:

Cov.:

AF XY:

0.0000222

AC XY:

AN XY:

721874

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV

Uncertain:1

Apr 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Uncertain:1

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1355 of the CACNA1H protein (p.Gly1355Ser). This variant is present in population databases (rs747715176, gnomAD 0.01%). 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: 579864). 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 expected to disrupt CACNA1H protein function with a positive 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

0.22

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;.

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;.;M;M

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.4

D;.;D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

D;.;D;D

Sift4G

Uncertain

0.013

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.75

MutPred

0.47

Gain of disorder (P = 0.0638);.;Gain of disorder (P = 0.0638);Gain of disorder (P = 0.0638);

MVP

0.98

ClinPred

0.92

GERP RS

4.2

Varity_R

0.75

gMVP

0.79

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

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