rs1180154075

Variant names:

Variant summary

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

The NM_021098.3(CACNA1H):c.2001T>A(p.His667Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,486,336 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/24 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 missense, splice_region

Scores

Splicing: ADA: 0.00004963

Clinical Significance

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

Conservation

PhyloP100: -1.23

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04928428).

BP6

Variant 16-1202451-T-A is Benign according to our data. Variant chr16-1202451-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529559.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000135 (18/1334192) while in subpopulation AMR AF = 0.000544 (17/31238). AF 95% confidence interval is 0.000347. There are 1 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.2001T>A	p.His667Gln	missense_variant, splice_region_variant	Exon 9 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.2001T>A	p.His667Gln	missense_variant, splice_region_variant	Exon 9 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.2001T>A	p.His667Gln	missense_variant, splice_region_variant	Exon 9 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.2001T>A	p.His667Gln	missense_variant, splice_region_variant	Exon 9 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.2001T>A	p.His667Gln	missense_variant, splice_region_variant	Exon 9 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.2001T>A	p.His667Gln	missense_variant, splice_region_variant	Exon 9 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.2001T>A	p.His667Gln	missense_variant, splice_region_variant	Exon 9 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.1962T>A	p.His654Gln	missense_variant, splice_region_variant	Exon 9 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.2001T>A	p.His667Gln	missense_variant, splice_region_variant	Exon 9 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.1962T>A	p.His654Gln	missense_variant, splice_region_variant	Exon 9 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.2001T>A	p.His667Gln	missense_variant, splice_region_variant	Exon 9 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.2001T>A	p.His667Gln	missense_variant, splice_region_variant	Exon 9 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.2001T>A	p.His667Gln	missense_variant, splice_region_variant	Exon 9 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.2001T>A	p.His667Gln	missense_variant, splice_region_variant	Exon 9 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.2001T>A	p.His667Gln	missense_variant, splice_region_variant	Exon 9 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.2001T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.2001T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.2001T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000711442.1 link	n.*1448T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.2001T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.2001T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.2001T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.2001T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.2001T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.2001T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.2001T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.2001T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.2001T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*1448T>A		3_prime_UTR_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000640028.1 link	n.1385+616T>A		intron_variant	Intron 9 of 34	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000139

AC:

AN:

100786

AF XY:

0.0000572

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000692

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000135

AC:

AN:

1334192

Hom.:

Cov.:

AF XY:

0.00000769

AC XY:

AN XY:

649956

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30364

American (AMR)

AF:

0.000544

AC:

AN:

31238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21678

East Asian (EAS)

AF:

0.00

AC:

AN:

35076

South Asian (SAS)

AF:

0.00

AC:

AN:

70404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5390

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1046166

Other (OTH)

AF:

0.0000181

AC:

AN:

55358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

152144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41516

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67964

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

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

May 18, 2022

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

May 17, 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

0.15

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.25

CADD

Benign

1.1

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.12

T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.54

T;T;T;.

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.049

T;T;T;T

MetaSVM

Uncertain

0.0010

MutationAssessor

Benign

0.69

N;.;N;N

PhyloP100

-1.2

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.4

N;.;N;N

REVEL

Benign

0.26

Sift

Benign

1.0

T;.;T;T

Sift4G

Benign

0.56

T;.;T;T

Polyphen

0.017

B;.;B;B

Vest4

0.20

MutPred

0.32

Loss of catalytic residue at G668 (P = 0.098);.;Loss of catalytic residue at G668 (P = 0.098);Loss of catalytic residue at G668 (P = 0.098);

MVP

0.70

ClinPred

0.032

GERP RS

-4.1

Varity_R

0.077

gMVP

0.38

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000050

dbscSNV1_RF

Benign

0.058

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