16-1215062-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_021098.3(CACNA1H):c.5020C>T(p.Arg1674Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,612,306 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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. R1674H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.49

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: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5020C>T	p.Arg1674Cys	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.5020C>T	p.Arg1674Cys	missense_variant	Exon 28 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.5035C>T	p.Arg1679Cys	missense_variant	Exon 27 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.5038C>T	p.Arg1680Cys	missense_variant	Exon 27 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5002C>T	p.Arg1668Cys	missense_variant	Exon 27 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.5035C>T	p.Arg1679Cys	missense_variant	Exon 28 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5020C>T	p.Arg1674Cys	missense_variant	Exon 28 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4981C>T	p.Arg1661Cys	missense_variant	Exon 28 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.5002C>T	p.Arg1668Cys	missense_variant	Exon 27 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4963C>T	p.Arg1655Cys	missense_variant	Exon 27 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5020C>T	p.Arg1674Cys	missense_variant	Exon 28 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5002C>T	p.Arg1668Cys	missense_variant	Exon 27 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5020C>T	p.Arg1674Cys	missense_variant	Exon 28 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5020C>T	p.Arg1674Cys	missense_variant	Exon 28 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.5020C>T	p.Arg1674Cys	missense_variant	Exon 28 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.5020C>T		non_coding_transcript_exon_variant	Exon 28 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*972C>T		non_coding_transcript_exon_variant	Exon 27 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*101C>T		non_coding_transcript_exon_variant	Exon 28 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2871C>T		non_coding_transcript_exon_variant	Exon 28 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4464C>T		non_coding_transcript_exon_variant	Exon 26 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.5002C>T		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.5002C>T		non_coding_transcript_exon_variant	Exon 27 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*21C>T		non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.5020C>T		non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.5020C>T		non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5002C>T		non_coding_transcript_exon_variant	Exon 27 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5020C>T		non_coding_transcript_exon_variant	Exon 28 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5020C>T		non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*21C>T		non_coding_transcript_exon_variant	Exon 27 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*972C>T		3_prime_UTR_variant	Exon 27 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*101C>T		3_prime_UTR_variant	Exon 28 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2871C>T		3_prime_UTR_variant	Exon 28 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4464C>T		3_prime_UTR_variant	Exon 26 of 34			ENSP00000518758.1
CACNA1H	ENST00000711451.1 link	n.*21C>T		3_prime_UTR_variant	Exon 28 of 36			ENSP00000518763.1
CACNA1H	ENST00000711488.1 link	n.*21C>T		3_prime_UTR_variant	Exon 27 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000204

AC:

AN:

245418

AF XY:

0.0000150

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.0000360

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1460206

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726248

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44536

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85972

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111254

Other (OTH)

AF:

0.0000332

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.0000329

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74294

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000483

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000268), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.395

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:

0.000116

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 29, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5020C>T (p.R1674C) alteration is located in exon 28 (coding exon 27) of the CACNA1H gene. This alteration results from a C to T substitution at nucleotide position 5020, causing the arginine (R) at amino acid position 1674 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Nov 27, 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 cysteine, which is neutral and slightly polar, at codon 1674 of the CACNA1H protein (p.Arg1674Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 460136). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

D;D;D;.

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;.;.;.

PhyloP100

2.5

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.7

D;.;D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0030

D;.;D;D

Sift4G

Pathogenic

0.0

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.70

MVP

0.98

ClinPred

0.89

GERP RS

4.0

Varity_R

0.69

gMVP

0.77

Mutation Taster

=38/62

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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