rs149367557

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_021098.3(CACNA1H):c.5024G>A(p.Arg1675Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000962 in 1,611,924 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. R1675L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.91

Publications

8 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 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5024G>A	p.Arg1675Gln	missense_variant	Exon 28 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.5024G>A	p.Arg1675Gln	missense_variant	Exon 28 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.5039G>A	p.Arg1680Gln	missense_variant	Exon 27 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.5042G>A	p.Arg1681Gln	missense_variant	Exon 27 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5006G>A	p.Arg1669Gln	missense_variant	Exon 27 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.5039G>A	p.Arg1680Gln	missense_variant	Exon 28 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5024G>A	p.Arg1675Gln	missense_variant	Exon 28 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4985G>A	p.Arg1662Gln	missense_variant	Exon 28 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.5006G>A	p.Arg1669Gln	missense_variant	Exon 27 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4967G>A	p.Arg1656Gln	missense_variant	Exon 27 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5024G>A	p.Arg1675Gln	missense_variant	Exon 28 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5006G>A	p.Arg1669Gln	missense_variant	Exon 27 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5024G>A	p.Arg1675Gln	missense_variant	Exon 28 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5024G>A	p.Arg1675Gln	missense_variant	Exon 28 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.5024G>A	p.Arg1675Gln	missense_variant	Exon 28 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.5024G>A		non_coding_transcript_exon_variant	Exon 28 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*976G>A		non_coding_transcript_exon_variant	Exon 27 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*105G>A		non_coding_transcript_exon_variant	Exon 28 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2875G>A		non_coding_transcript_exon_variant	Exon 28 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4468G>A		non_coding_transcript_exon_variant	Exon 26 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.5006G>A		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.5006G>A		non_coding_transcript_exon_variant	Exon 27 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*25G>A		non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.5024G>A		non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.5024G>A		non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5006G>A		non_coding_transcript_exon_variant	Exon 27 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5024G>A		non_coding_transcript_exon_variant	Exon 28 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5024G>A		non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*25G>A		non_coding_transcript_exon_variant	Exon 27 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*976G>A		3_prime_UTR_variant	Exon 27 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*105G>A		3_prime_UTR_variant	Exon 28 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2875G>A		3_prime_UTR_variant	Exon 28 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4468G>A		3_prime_UTR_variant	Exon 26 of 34			ENSP00000518758.1
CACNA1H	ENST00000711451.1 link	n.*25G>A		3_prime_UTR_variant	Exon 28 of 36			ENSP00000518763.1
CACNA1H	ENST00000711488.1 link	n.*25G>A		3_prime_UTR_variant	Exon 27 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000123

AC:

AN:

244404

AF XY:

0.000120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000203

Gnomad EAS exome

AF:

0.000561

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000154

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000973

AC:

142

AN:

1459654

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

725914

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.0000450

AC:

AN:

44480

Ashkenazi Jewish (ASJ)

AF:

0.000269

AC:

AN:

26044

East Asian (EAS)

AF:

0.000277

AC:

AN:

39656

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53120

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000104

AC:

115

AN:

1111022

Other (OTH)

AF:

0.0000663

AC:

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.0000854

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41558

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.000121

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000191

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1675 of the CACNA1H protein (p.Arg1675Gln). This variant is present in population databases (rs149367557, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with seizures (PMID: 27066544). This variant is also known as p.Arg1669Gln. ClinVar contains an entry for this variant (Variation ID: 571604). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

not provided

Uncertain:1

Jun 15, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with epilepsy with auditory features who inherited the variant from a parent with sleep-related bilateral tonic-clonic seizures (Pippucci et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27066544) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;.;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

D;D;D;.

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.51

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.0

M;.;.;.

PhyloP100

7.9

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.9

D;.;D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0090

D;.;D;D

Sift4G

Uncertain

0.037

D;.;D;D

Polyphen

0.90

P;.;D;D

Vest4

0.69

MVP

0.96

ClinPred

0.40

GERP RS

4.0

Varity_R

0.72

gMVP

0.68

Mutation Taster

=29/71

disease causing

(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