chr16-1212137-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The ENST00000711450.1(CACNA1H):c.4696G>A(p.Glu1566Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000073 in 1,603,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 6/8 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. E1566E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

CACNA1H
ENST00000711450.1 missense, splice_region

Scores

Splicing: ADA: 0.6922

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 5.40

Publications

0 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 16-1212137-G-A is Benign according to our data. Variant chr16-1212137-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 460123.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000295 (45/152304) while in subpopulation AFR AF = 0.00106 (44/41562). AF 95% confidence interval is 0.00081. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4758G>A	p.Arg1586Arg	splice_region_variant, synonymous_variant	Exon 25 of 35	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000711450.1 link	c.4696G>A	p.Glu1566Lys	missense_variant, splice_region_variant	Exon 25 of 35			ENSP00000518762.1
CACNA1H	ENST00000348261.11 link	c.4758G>A	p.Arg1586Arg	splice_region_variant, synonymous_variant	Exon 25 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4758G>A	p.Arg1586Arg	synonymous_variant	Exon 25 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4794G>A	p.Arg1598Arg	splice_region_variant, synonymous_variant	Exon 25 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4758G>A	p.Arg1586Arg	splice_region_variant, synonymous_variant	Exon 25 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000564231.6 link	c.4758G>A	p.Arg1586Arg	splice_region_variant, synonymous_variant	Exon 25 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4719G>A	p.Arg1573Arg	splice_region_variant, synonymous_variant	Exon 25 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4758G>A	p.Arg1586Arg	splice_region_variant, synonymous_variant	Exon 25 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4719G>A	p.Arg1573Arg	splice_region_variant, synonymous_variant	Exon 25 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4758G>A	p.Arg1586Arg	splice_region_variant, synonymous_variant	Exon 25 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4758G>A	p.Arg1586Arg	splice_region_variant, synonymous_variant	Exon 25 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4758G>A	p.Arg1586Arg	splice_region_variant, synonymous_variant	Exon 25 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4758G>A	p.Arg1586Arg	splice_region_variant, synonymous_variant	Exon 25 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4758G>A	p.Arg1586Arg	splice_region_variant, synonymous_variant	Exon 25 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4758G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 25 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*728G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 25 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4696G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 25 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2609G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 25 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4143G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 24 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4758G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4758G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 25 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4758G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4758G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4758G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4758G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 25 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4758G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 25 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4758G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4758G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 25 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*728G>A		3_prime_UTR_variant	Exon 25 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2609G>A		3_prime_UTR_variant	Exon 25 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4143G>A		3_prime_UTR_variant	Exon 24 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000632

AC:

AN:

237468

AF XY:

0.0000461

show subpopulations

Gnomad AFR exome

AF:

0.000937

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000923

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000496

AC:

AN:

1450858

Hom.:

Cov.:

AF XY:

0.0000402

AC XY:

AN XY:

721856

show subpopulations

African (AFR)

AF:

0.000779

AC:

AN:

33376

American (AMR)

AF:

0.0000224

AC:

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26050

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45838

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4742

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

1110470

Other (OTH)

AF:

0.0000499

AC:

AN:

60076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000295

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

41562

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

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

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:

0.000120

Hom.:

Bravo

AF:

0.000257

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CACNA1H-related disorder

Benign:1

Feb 22, 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

Jun 04, 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

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

5.4

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.69

dbscSNV1_RF

Benign

0.36

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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