16-1207426-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_021098.3(CACNA1H):c.3059C>T(p.Ala1020Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,612,346 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1020E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.01

Publications

1 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 -3 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BS2

High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3059C>T	p.Ala1020Val	missense_variant	Exon 14 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.3059C>T	p.Ala1020Val	missense_variant	Exon 14 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3059C>T	p.Ala1020Val	missense_variant	Exon 14 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3059C>T	p.Ala1020Val	missense_variant	Exon 14 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3059C>T	p.Ala1020Val	missense_variant	Exon 14 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3059C>T	p.Ala1020Val	missense_variant	Exon 14 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3059C>T	p.Ala1020Val	missense_variant	Exon 14 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3020C>T	p.Ala1007Val	missense_variant	Exon 14 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3059C>T	p.Ala1020Val	missense_variant	Exon 14 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3020C>T	p.Ala1007Val	missense_variant	Exon 14 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3059C>T	p.Ala1020Val	missense_variant	Exon 14 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3059C>T	p.Ala1020Val	missense_variant	Exon 14 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3059C>T	p.Ala1020Val	missense_variant	Exon 14 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3059C>T	p.Ala1020Val	missense_variant	Exon 14 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3059C>T	p.Ala1020Val	missense_variant	Exon 14 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3059C>T		non_coding_transcript_exon_variant	Exon 14 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3059C>T		non_coding_transcript_exon_variant	Exon 14 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3059C>T		non_coding_transcript_exon_variant	Exon 14 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*972C>T		non_coding_transcript_exon_variant	Exon 14 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2506C>T		non_coding_transcript_exon_variant	Exon 13 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3059C>T		non_coding_transcript_exon_variant	Exon 14 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3059C>T		non_coding_transcript_exon_variant	Exon 14 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3059C>T		non_coding_transcript_exon_variant	Exon 14 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3059C>T		non_coding_transcript_exon_variant	Exon 14 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3059C>T		non_coding_transcript_exon_variant	Exon 14 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3059C>T		non_coding_transcript_exon_variant	Exon 14 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3059C>T		non_coding_transcript_exon_variant	Exon 14 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3059C>T		non_coding_transcript_exon_variant	Exon 14 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3059C>T		non_coding_transcript_exon_variant	Exon 14 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*972C>T		3_prime_UTR_variant	Exon 14 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2506C>T		3_prime_UTR_variant	Exon 13 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000243

AC:

AN:

247050

AF XY:

0.0000297

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000269

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1460574

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

726566

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.0000448

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1111718

Other (OTH)

AF:

0.0000166

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.0000132

AC:

AN:

151772

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74120

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41288

American (AMR)

AF:

0.0000656

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67936

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000166

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Jun 20, 2024

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

Jul 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1020 of the CACNA1H protein (p.Ala1020Val). This variant is present in population databases (rs771994752, gnomAD 0.009%). 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: 2026123). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1H protein function. 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

0.23

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;.;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D;.

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.77

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;.;M;M

PhyloP100

6.0

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.1

D;.;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0090

D;.;D;D

Sift4G

Uncertain

0.0030

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.68

MutPred

0.39

Loss of disorder (P = 0.0725);.;Loss of disorder (P = 0.0725);Loss of disorder (P = 0.0725);

MVP

0.96

ClinPred

0.89

GERP RS

3.6

Varity_R

0.58

gMVP

0.45

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.52

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.52

Position offset: -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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over