rs369045626

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 4P and 6B. PM1PP3_ModerateBP6_ModerateBS2

The NM_021098.3(CACNA1H):c.4651G>A(p.Val1551Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1551L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 9.63

Publications

4 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: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_021098.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.844

BP6

Variant 16-1212030-G-A is Benign according to our data. Variant chr16-1212030-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 460122.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4651G>A	p.Val1551Met	missense_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	ENST00000348261.11 link	c.4651G>A	p.Val1551Met	missense_variant	Exon 25 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4651G>A	p.Val1551Met	missense_variant	Exon 25 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4687G>A	p.Val1563Met	missense_variant	Exon 25 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4651G>A	p.Val1551Met	missense_variant	Exon 25 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4589G>A	p.Arg1530His	missense_variant	Exon 25 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4651G>A	p.Val1551Met	missense_variant	Exon 25 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4612G>A	p.Val1538Met	missense_variant	Exon 25 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4651G>A	p.Val1551Met	missense_variant	Exon 25 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4612G>A	p.Val1538Met	missense_variant	Exon 25 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4651G>A	p.Val1551Met	missense_variant	Exon 25 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4651G>A	p.Val1551Met	missense_variant	Exon 25 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4651G>A	p.Val1551Met	missense_variant	Exon 25 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4651G>A	p.Val1551Met	missense_variant	Exon 25 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4651G>A	p.Val1551Met	missense_variant	Exon 25 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4651G>A		non_coding_transcript_exon_variant	Exon 25 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*621G>A		non_coding_transcript_exon_variant	Exon 25 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4589G>A		non_coding_transcript_exon_variant	Exon 25 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2502G>A		non_coding_transcript_exon_variant	Exon 25 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4036G>A		non_coding_transcript_exon_variant	Exon 24 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4651G>A		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4651G>A		non_coding_transcript_exon_variant	Exon 25 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4651G>A		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4651G>A		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4651G>A		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4651G>A		non_coding_transcript_exon_variant	Exon 25 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4651G>A		non_coding_transcript_exon_variant	Exon 25 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4651G>A		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4651G>A		non_coding_transcript_exon_variant	Exon 25 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*621G>A		3_prime_UTR_variant	Exon 25 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2502G>A		3_prime_UTR_variant	Exon 25 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4036G>A		3_prime_UTR_variant	Exon 24 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

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:

0.0000522

AC:

AN:

248988

AF XY:

0.0000592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000994

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461086

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726840

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000689

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111672

Other (OTH)

AF:

0.0000663

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.0000394

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000675

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CACNA1H p.Val1551Met variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs369045626) and in ClinVar (classified as uncertain significance by Invitae for Idiopathic generalized epilepsy and Hyperaldosteronism, familial, type IV). The variant was also identified in control databases in 13 of 248988 chromosomes at a frequency of 0.000052 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 10 of 10058 chromosomes (freq: 0.000994), Other in 2 of 6048 chromosomes (freq: 0.000331) and East Asian in 1 of 17972 chromosomes (freq: 0.000056), but was not observed in the African, Latino, European (Finnish), European (non-Finnish) or South Asian populations. The p.Val1551 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

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

Benign:1

Sep 03, 2023

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

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

1.0

D;D;D;.

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Pathogenic

1.0

PhyloP100

9.6

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.6

D;.;D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0010

D;.;D;D

Polyphen

0.99

D;.;D;D

Vest4

0.82

MVP

0.96

ClinPred

0.89

GERP RS

4.1

Varity_R

0.81

gMVP

0.68

Mutation Taster

=40/60

disease causing

(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

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