NM_021098.3:c.2329C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_021098.3(CACNA1H):c.2329C>T(p.Arg777Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,590,280 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R777H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 2 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.14

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: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2559896).

BP6

Variant 16-1204336-C-T is Benign according to our data. Variant chr16-1204336-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 580279.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000139 (200/1437908) while in subpopulation MID AF = 0.0085 (48/5644). AF 95% confidence interval is 0.00659. There are 2 homozygotes in GnomAdExome4. There are 95 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.2329C>T	p.Arg777Cys	missense_variant	Exon 10 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.2329C>T	p.Arg777Cys	missense_variant	Exon 10 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.2329C>T	p.Arg777Cys	missense_variant	Exon 10 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.2329C>T	p.Arg777Cys	missense_variant	Exon 10 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.2329C>T	p.Arg777Cys	missense_variant	Exon 10 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.2329C>T	p.Arg777Cys	missense_variant	Exon 10 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.2329C>T	p.Arg777Cys	missense_variant	Exon 10 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.2290C>T	p.Arg764Cys	missense_variant	Exon 10 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.2329C>T	p.Arg777Cys	missense_variant	Exon 10 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.2290C>T	p.Arg764Cys	missense_variant	Exon 10 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.2329C>T	p.Arg777Cys	missense_variant	Exon 10 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.2329C>T	p.Arg777Cys	missense_variant	Exon 10 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.2329C>T	p.Arg777Cys	missense_variant	Exon 10 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.2329C>T	p.Arg777Cys	missense_variant	Exon 10 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.2329C>T	p.Arg777Cys	missense_variant	Exon 10 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.2329C>T		non_coding_transcript_exon_variant	Exon 10 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.2329C>T		non_coding_transcript_exon_variant	Exon 10 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.2329C>T		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*242C>T		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*1776C>T		non_coding_transcript_exon_variant	Exon 9 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.2329C>T		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.2329C>T		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.2329C>T		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.2329C>T		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.2329C>T		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.2329C>T		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.2329C>T		non_coding_transcript_exon_variant	Exon 10 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.2329C>T		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.2329C>T		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*242C>T		3_prime_UTR_variant	Exon 10 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*1776C>T		3_prime_UTR_variant	Exon 9 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000126

AC:

AN:

229254

AF XY:

0.000128

show subpopulations

Gnomad AFR exome

AF:

0.000271

Gnomad AMR exome

AF:

0.0000934

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000495

Gnomad NFE exome

AF:

0.000183

Gnomad OTH exome

AF:

0.000182

GnomAD4 exome

AF:

0.000139

AC:

200

AN:

1437908

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

712246

show subpopulations

African (AFR)

AF:

0.000213

AC:

AN:

32896

American (AMR)

AF:

0.0000944

AC:

AN:

42378

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24816

East Asian (EAS)

AF:

0.00

AC:

AN:

39304

South Asian (SAS)

AF:

0.0000481

AC:

AN:

83242

European-Finnish (FIN)

AF:

0.0000391

AC:

AN:

51194

Middle Eastern (MID)

AF:

0.00850

AC:

AN:

5644

European-Non Finnish (NFE)

AF:

0.000108

AC:

119

AN:

1099174

Other (OTH)

AF:

0.000270

AC:

AN:

59260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000171

AC:

AN:

152372

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41586

American (AMR)

AF:

0.0000653

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

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:

0.000143

Hom.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000100

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Oct 31, 2018

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

Benign:1

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.24

T;.;.;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.78

T;T;T;.

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Uncertain

0.042

MutationAssessor

Uncertain

2.1

M;.;M;M

PhyloP100

1.1

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.6

N;.;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.044

D;.;D;D

Sift4G

Benign

0.093

T;.;T;T

Polyphen

0.0040

B;.;B;B

Vest4

0.17

MVP

0.62

ClinPred

0.014

GERP RS

3.2

Varity_R

0.15

gMVP

0.42

Mutation Taster

=91/9

polymorphism

(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