rs375982567

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_021098.3(CACNA1H):c.546-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,610,834 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 intron

Scores

Splicing: ADA: 0.00009122

Clinical Significance

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

Conservation

PhyloP100: -0.0790

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 16-1195917-C-T is Benign according to our data. Variant chr16-1195917-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529627.

BS2

High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.546-9C>T		intron_variant	Intron 4 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.546-9C>T	intron_variant	Intron 4 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.546-9C>T	intron_variant	Intron 4 of 33	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.546-9C>T	intron_variant	Intron 4 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.546-9C>T	intron_variant	Intron 4 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.546-9C>T	intron_variant	Intron 4 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.546-9C>T	intron_variant	Intron 4 of 34	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.507-9C>T	intron_variant	Intron 4 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.546-9C>T	intron_variant	Intron 4 of 33	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.507-9C>T	intron_variant	Intron 4 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.546-9C>T	intron_variant	Intron 4 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.546-9C>T	intron_variant	Intron 4 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.546-9C>T	intron_variant	Intron 4 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.546-9C>T	intron_variant	Intron 4 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.546-9C>T	intron_variant	Intron 4 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.546-9C>T	intron_variant	Intron 4 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.546-9C>T	intron_variant	Intron 4 of 33	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.546-9C>T	intron_variant	Intron 4 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.546-9C>T	intron_variant	Intron 4 of 34	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*90+258C>T	intron_variant	Intron 4 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.546-9C>T	intron_variant	Intron 4 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.546-9C>T	intron_variant	Intron 4 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.546-9C>T	intron_variant	Intron 4 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.546-9C>T	intron_variant	Intron 4 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.546-9C>T	intron_variant	Intron 4 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.546-9C>T	intron_variant	Intron 4 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.546-9C>T	intron_variant	Intron 4 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.546-9C>T	intron_variant	Intron 4 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.546-9C>T	intron_variant	Intron 4 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000162

AC:

AN:

247472

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1458604

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

725764

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33422

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.000176

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1109954

Other (OTH)

AF:

0.0000166

AC:

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

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:

0.00000657

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2094

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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

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

Feb 09, 2024

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

Apr 25, 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

-0.81

CADD

Benign

4.6

(source)

DANN

Benign

0.61

PhyloP100

-0.079

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000091

dbscSNV1_RF

Benign

0.012

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over