rs111986908

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_021098.3(CACNA1H):c.2229G>A(p.Thr743Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000852 in 1,611,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00088 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.59

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 16-1204236-G-A is Benign according to our data. Variant chr16-1204236-G-A is described in ClinVar as [Benign]. Clinvar id is 529639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.6 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000584 (89/152322) while in subpopulation AMR AF = 0.00105 (16/15308). AF 95% confidence interval is 0.000742. There are 0 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 89 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.2229G>A	p.Thr743Thr	synonymous_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.2229G>A	p.Thr743Thr	synonymous_variant	Exon 10 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.2229G>A	p.Thr743Thr	synonymous_variant	Exon 10 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.2229G>A	p.Thr743Thr	synonymous_variant	Exon 10 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.2229G>A	p.Thr743Thr	synonymous_variant	Exon 10 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.2229G>A	p.Thr743Thr	synonymous_variant	Exon 10 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.2229G>A	p.Thr743Thr	synonymous_variant	Exon 10 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.2190G>A	p.Thr730Thr	synonymous_variant	Exon 10 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.2229G>A	p.Thr743Thr	synonymous_variant	Exon 10 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.2190G>A	p.Thr730Thr	synonymous_variant	Exon 10 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.2229G>A	p.Thr743Thr	synonymous_variant	Exon 10 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.2229G>A	p.Thr743Thr	synonymous_variant	Exon 10 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.2229G>A	p.Thr743Thr	synonymous_variant	Exon 10 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.2229G>A	p.Thr743Thr	synonymous_variant	Exon 10 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.2229G>A	p.Thr743Thr	synonymous_variant	Exon 10 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.2229G>A		non_coding_transcript_exon_variant	Exon 10 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.2229G>A		non_coding_transcript_exon_variant	Exon 10 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.2229G>A		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*142G>A		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*1676G>A		non_coding_transcript_exon_variant	Exon 9 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.2229G>A		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.2229G>A		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.2229G>A		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.2229G>A		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.2229G>A		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.2229G>A		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.2229G>A		non_coding_transcript_exon_variant	Exon 10 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.2229G>A		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.2229G>A		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*142G>A		3_prime_UTR_variant	Exon 10 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*1676G>A		3_prime_UTR_variant	Exon 9 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000533

AC:

128

AN:

240174

AF XY:

0.000539

show subpopulations

Gnomad AFR exome

AF:

0.000345

Gnomad AMR exome

AF:

0.000205

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.000340

GnomAD4 exome

AF:

0.000879

AC:

1283

AN:

1458784

Hom.:

Cov.:

AF XY:

0.000852

AC XY:

618

AN XY:

725632

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33434

American (AMR)

AF:

0.000180

AC:

AN:

44548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86018

European-Finnish (FIN)

AF:

0.0000386

AC:

AN:

51878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00110

AC:

1223

AN:

1111180

Other (OTH)

AF:

0.000664

AC:

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

165

247

330

412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000584

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41566

American (AMR)

AF:

0.00105

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000926

AC:

AN:

68012

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00109

Hom.:

Bravo

AF:

0.000684

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

4.3

(source)

DANN

Benign

0.82

PhyloP100

1.6

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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rs111986908

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