16-1215556-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_021098.3(CACNA1H):c.5207G>A(p.Arg1736His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,611,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. R1736C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.98

Publications

4 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 -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.897

BS2

High AC in GnomAdExome4 at 69 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5207G>A	p.Arg1736His	missense_variant	Exon 30 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.5207G>A	p.Arg1736His	missense_variant	Exon 30 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.5222G>A	p.Arg1741His	missense_variant	Exon 29 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.5225G>A	p.Arg1742His	missense_variant	Exon 29 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5189G>A	p.Arg1730His	missense_variant	Exon 29 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.5222G>A	p.Arg1741His	missense_variant	Exon 30 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5207G>A	p.Arg1736His	missense_variant	Exon 30 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.5168G>A	p.Arg1723His	missense_variant	Exon 30 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.5189G>A	p.Arg1730His	missense_variant	Exon 29 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.5150G>A	p.Arg1717His	missense_variant	Exon 29 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5207G>A	p.Arg1736His	missense_variant	Exon 30 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5189G>A	p.Arg1730His	missense_variant	Exon 29 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5207G>A	p.Arg1736His	missense_variant	Exon 30 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5207G>A	p.Arg1736His	missense_variant	Exon 30 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.5207G>A	p.Arg1736His	missense_variant	Exon 30 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.5207G>A		non_coding_transcript_exon_variant	Exon 30 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1159G>A		non_coding_transcript_exon_variant	Exon 29 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*288G>A		non_coding_transcript_exon_variant	Exon 30 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3058G>A		non_coding_transcript_exon_variant	Exon 30 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4651G>A		non_coding_transcript_exon_variant	Exon 28 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.5189G>A		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.5189G>A		non_coding_transcript_exon_variant	Exon 29 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*208G>A		non_coding_transcript_exon_variant	Exon 30 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.5207G>A		non_coding_transcript_exon_variant	Exon 30 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.5207G>A		non_coding_transcript_exon_variant	Exon 30 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5189G>A		non_coding_transcript_exon_variant	Exon 29 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5207G>A		non_coding_transcript_exon_variant	Exon 30 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5207G>A		non_coding_transcript_exon_variant	Exon 30 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*208G>A		non_coding_transcript_exon_variant	Exon 29 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*1159G>A		3_prime_UTR_variant	Exon 29 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*288G>A		3_prime_UTR_variant	Exon 30 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3058G>A		3_prime_UTR_variant	Exon 30 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4651G>A		3_prime_UTR_variant	Exon 28 of 34			ENSP00000518758.1
CACNA1H	ENST00000711451.1 link	n.*208G>A		3_prime_UTR_variant	Exon 30 of 36			ENSP00000518763.1
CACNA1H	ENST00000711488.1 link	n.*208G>A		3_prime_UTR_variant	Exon 29 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152222

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000286

AC:

AN:

244798

AF XY:

0.0000225

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000363

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000473

AC:

AN:

1459548

Hom.:

Cov.:

AF XY:

0.0000510

AC XY:

AN XY:

726028

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33464

American (AMR)

AF:

0.0000224

AC:

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000531

AC:

AN:

1111554

Other (OTH)

AF:

0.0000663

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.0000197

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

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

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:

0.0000868

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000249

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Nov 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. 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. ClinVar contains an entry for this variant (Variation ID: 460140). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. This variant is present in population databases (rs3889063, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1736 of the CACNA1H protein (p.Arg1736His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D;.;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.99

D;D;D;.

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.;.;.

PhyloP100

8.0

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.0

D;.;D;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.75

MutPred

0.73

Loss of MoRF binding (P = 0.0195);.;.;.;

MVP

0.96

ClinPred

0.99

GERP RS

3.6

Varity_R

0.88

gMVP

0.79

Mutation Taster

=49/51

disease causing

(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