rs59286323

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021098.3(CACNA1H):c.4817C>T(p.Thr1606Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 1,584,426 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1606T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0048 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 54 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.994

Publications

9 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014217705).

BP6

Variant 16-1213819-C-T is Benign according to our data. Variant chr16-1213819-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00479 (729/152210) while in subpopulation NFE AF = 0.00806 (548/67982). AF 95% confidence interval is 0.0075. There are 2 homozygotes in GnomAd4. There are 344 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 729 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4817C>T	p.Thr1606Met	missense_variant	Exon 27 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.4817C>T	p.Thr1606Met	missense_variant	Exon 27 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4832C>T	p.Thr1611Met	missense_variant	Exon 26 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4835C>T	p.Thr1612Met	missense_variant	Exon 26 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4799C>T	p.Thr1600Met	missense_variant	Exon 26 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4832C>T	p.Thr1611Met	missense_variant	Exon 27 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4817C>T	p.Thr1606Met	missense_variant	Exon 27 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4778C>T	p.Thr1593Met	missense_variant	Exon 27 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4799C>T	p.Thr1600Met	missense_variant	Exon 26 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4760C>T	p.Thr1587Met	missense_variant	Exon 26 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4817C>T	p.Thr1606Met	missense_variant	Exon 27 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4799C>T	p.Thr1600Met	missense_variant	Exon 26 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4817C>T	p.Thr1606Met	missense_variant	Exon 27 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4817C>T	p.Thr1606Met	missense_variant	Exon 27 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4817C>T	p.Thr1606Met	missense_variant	Exon 27 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4817C>T		non_coding_transcript_exon_variant	Exon 27 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*769C>T		non_coding_transcript_exon_variant	Exon 26 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4755C>T		non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2668C>T		non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4261C>T		non_coding_transcript_exon_variant	Exon 25 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4799C>T		non_coding_transcript_exon_variant	Exon 26 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4799C>T		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4894C>T		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4817C>T		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4817C>T		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4799C>T		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4817C>T		non_coding_transcript_exon_variant	Exon 27 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4817C>T		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4876C>T		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*769C>T		3_prime_UTR_variant	Exon 26 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2668C>T		3_prime_UTR_variant	Exon 27 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4261C>T		3_prime_UTR_variant	Exon 25 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.00480

AC:

730

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00490

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00806

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00501

AC:

1010

AN:

201458

AF XY:

0.00519

show subpopulations

Gnomad AFR exome

AF:

0.00130

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.000762

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00435

Gnomad NFE exome

AF:

0.00797

Gnomad OTH exome

AF:

0.00667

GnomAD4 exome

AF:

0.00720

AC:

10312

AN:

1432216

Hom.:

Cov.:

AF XY:

0.00715

AC XY:

5073

AN XY:

709850

show subpopulations

African (AFR)

AF:

0.00112

AC:

AN:

32998

American (AMR)

AF:

0.00239

AC:

AN:

39740

Ashkenazi Jewish (ASJ)

AF:

0.00121

AC:

AN:

25626

East Asian (EAS)

AF:

0.00

AC:

AN:

38438

South Asian (SAS)

AF:

0.00389

AC:

320

AN:

82284

European-Finnish (FIN)

AF:

0.00474

AC:

233

AN:

49164

Middle Eastern (MID)

AF:

0.00175

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00842

AC:

9250

AN:

1098810

Other (OTH)

AF:

0.00565

AC:

336

AN:

59426

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

520

1039

1559

2078

2598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

350

700

1050

1400

1750

<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:

0.00479

AC:

729

AN:

152210

Hom.:

Cov.:

AF XY:

0.00462

AC XY:

344

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41564

American (AMR)

AF:

0.00301

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5116

South Asian (SAS)

AF:

0.00290

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00490

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00806

AC:

548

AN:

67982

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

104

139

174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00654

Hom.:

Bravo

AF:

0.00448

ESP6500AA

AF:

0.00195

AC:

ESP6500EA

AF:

0.00798

AC:

ExAC

AF:

0.00498

AC:

597

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 15, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Aug 14, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 05, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV

Benign:1

Dec 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

T;.;.;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.88

D;D;D;.

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Uncertain

0.47

PhyloP100

0.99

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.0

N;.;N;N

REVEL

Uncertain

0.50

Sift

Benign

0.22

T;.;T;T

Sift4G

Benign

0.24

T;.;T;T

Polyphen

0.28

B;.;P;P

Vest4

0.57

MVP

0.89

ClinPred

0.013

GERP RS

3.9

Varity_R

0.086

gMVP

0.58

Mutation Taster

=99/1

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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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