rs370039255

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_021098.3(CACNA1H):c.3555G>A(p.Ala1185Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,545,024 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1185A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -3.15

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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 16-1209223-G-A is Benign according to our data. Variant chr16-1209223-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96010.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000676 (103/152280) while in subpopulation AMR AF = 0.00118 (18/15306). AF 95% confidence interval is 0.000928. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3555G>A	p.Ala1185Ala	synonymous_variant	Exon 17 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.3555G>A	p.Ala1185Ala	synonymous_variant	Exon 17 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.3555G>A	p.Ala1185Ala	synonymous_variant	Exon 17 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.3555G>A	p.Ala1185Ala	synonymous_variant	Exon 17 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3555G>A	p.Ala1185Ala	synonymous_variant	Exon 17 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.3555G>A	p.Ala1185Ala	synonymous_variant	Exon 17 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3555G>A	p.Ala1185Ala	synonymous_variant	Exon 17 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.3516G>A	p.Ala1172Ala	synonymous_variant	Exon 17 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.3555G>A	p.Ala1185Ala	synonymous_variant	Exon 17 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.3516G>A	p.Ala1172Ala	synonymous_variant	Exon 17 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3555G>A	p.Ala1185Ala	synonymous_variant	Exon 17 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3555G>A	p.Ala1185Ala	synonymous_variant	Exon 17 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3555G>A	p.Ala1185Ala	synonymous_variant	Exon 17 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3555G>A	p.Ala1185Ala	synonymous_variant	Exon 17 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3555G>A	p.Ala1185Ala	synonymous_variant	Exon 17 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3555G>A		non_coding_transcript_exon_variant	Exon 17 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3555G>A		non_coding_transcript_exon_variant	Exon 17 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.3555G>A		non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*1468G>A		non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*3002G>A		non_coding_transcript_exon_variant	Exon 16 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3555G>A		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3555G>A		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3555G>A		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3555G>A		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3555G>A		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3555G>A		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3555G>A		non_coding_transcript_exon_variant	Exon 17 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3555G>A		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3555G>A		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*1468G>A		3_prime_UTR_variant	Exon 17 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*3002G>A		3_prime_UTR_variant	Exon 16 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

103

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.00113

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000739

AC:

102

AN:

137960

AF XY:

0.000596

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00164

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000195

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000977

Gnomad OTH exome

AF:

0.00146

GnomAD4 exome

AF:

0.00119

AC:

1659

AN:

1392744

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

801

AN XY:

687386

show subpopulations

African (AFR)

AF:

0.000227

AC:

AN:

30892

American (AMR)

AF:

0.00151

AC:

AN:

35732

Ashkenazi Jewish (ASJ)

AF:

0.0000400

AC:

AN:

25004

East Asian (EAS)

AF:

0.0000565

AC:

AN:

35394

South Asian (SAS)

AF:

0.000165

AC:

AN:

78944

European-Finnish (FIN)

AF:

0.0000446

AC:

AN:

44812

Middle Eastern (MID)

AF:

0.000352

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00139

AC:

1497

AN:

1078444

Other (OTH)

AF:

0.00140

AC:

AN:

57840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

115

231

346

462

577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.000676

AC:

103

AN:

152280

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41570

American (AMR)

AF:

0.00118

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00113

AC:

AN:

67998

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.000745

Hom.:

Bravo

AF:

0.000914

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jul 03, 2013

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BS1, BS2

CACNA1H-related disorder

Benign:1

Nov 12, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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

Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.13

(source)

DANN

Benign

0.76

PhyloP100

-3.2

Mutation Taster

=100/0

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