rs370088144

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021098.3(CACNA1H):c.2561G>A(p.Arg854Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,612,822 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R854W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.480

Publications

2 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.050218374).

BP6

Variant 16-1205223-G-A is Benign according to our data. Variant chr16-1205223-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 579739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00018 (263/1460508) while in subpopulation MID AF = 0.00278 (16/5760). AF 95% confidence interval is 0.00174. There are 1 homozygotes in GnomAdExome4. There are 143 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.2561G>A	p.Arg854Gln	missense_variant	Exon 11 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.2561G>A	p.Arg854Gln	missense_variant	Exon 11 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.2561G>A	p.Arg854Gln	missense_variant	Exon 11 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.2561G>A	p.Arg854Gln	missense_variant	Exon 11 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.2561G>A	p.Arg854Gln	missense_variant	Exon 11 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.2561G>A	p.Arg854Gln	missense_variant	Exon 11 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.2561G>A	p.Arg854Gln	missense_variant	Exon 11 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.2522G>A	p.Arg841Gln	missense_variant	Exon 11 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.2561G>A	p.Arg854Gln	missense_variant	Exon 11 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.2522G>A	p.Arg841Gln	missense_variant	Exon 11 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.2561G>A	p.Arg854Gln	missense_variant	Exon 11 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.2561G>A	p.Arg854Gln	missense_variant	Exon 11 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.2561G>A	p.Arg854Gln	missense_variant	Exon 11 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.2561G>A	p.Arg854Gln	missense_variant	Exon 11 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.2561G>A	p.Arg854Gln	missense_variant	Exon 11 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.2561G>A		non_coding_transcript_exon_variant	Exon 11 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.2561G>A		non_coding_transcript_exon_variant	Exon 11 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.2561G>A		non_coding_transcript_exon_variant	Exon 11 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*474G>A		non_coding_transcript_exon_variant	Exon 11 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2008G>A		non_coding_transcript_exon_variant	Exon 10 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.2561G>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.2561G>A		non_coding_transcript_exon_variant	Exon 11 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.2561G>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.2561G>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.2561G>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.2561G>A		non_coding_transcript_exon_variant	Exon 11 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.2561G>A		non_coding_transcript_exon_variant	Exon 11 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.2561G>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.2561G>A		non_coding_transcript_exon_variant	Exon 11 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*474G>A		3_prime_UTR_variant	Exon 11 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2008G>A		3_prime_UTR_variant	Exon 10 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000254

AC:

AN:

248454

AF XY:

0.000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00140

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000180

AC:

263

AN:

1460508

Hom.:

Cov.:

AF XY:

0.000197

AC XY:

143

AN XY:

726488

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.000358

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00138

AC:

AN:

26102

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52586

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000138

AC:

153

AN:

1111608

Other (OTH)

AF:

0.000481

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.000223

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41568

American (AMR)

AF:

0.000261

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68020

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000348

Hom.:

Bravo

AF:

0.000223

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000215

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000653

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BS1 -

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

Benign:1

Sep 06, 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

0.074

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.57

D;.;.;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.88

D;D;D;.

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.050

T;T;T;T

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

1.0

L;.;L;L

PhyloP100

0.48

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.9

N;.;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.20

T;.;T;T

Sift4G

Uncertain

0.040

D;.;D;D

Polyphen

0.67

P;.;B;B

Vest4

0.44

MVP

0.74

ClinPred

0.031

GERP RS

0.87

Varity_R

0.096

gMVP

0.42

Mutation Taster

=93/7

polymorphism

(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