16-1218596-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_021098.3(CACNA1H):c.5832C>T(p.His1944His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,564,796 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00025 ( 5 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.265

Publications

1 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 16-1218596-C-T is Benign according to our data. Variant chr16-1218596-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 529685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.265 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000368 (56/152202) while in subpopulation AMR AF = 0.0019 (29/15292). AF 95% confidence interval is 0.00136. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5832C>T	p.His1944His	synonymous_variant	Exon 33 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.5832C>T	p.His1944His	synonymous_variant	Exon 33 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.5847C>T	p.His1949His	synonymous_variant	Exon 32 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.5850C>T	p.His1950His	synonymous_variant	Exon 32 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5814C>T	p.His1938His	synonymous_variant	Exon 32 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.5847C>T	p.His1949His	synonymous_variant	Exon 33 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5832C>T	p.His1944His	synonymous_variant	Exon 33 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.5793C>T	p.His1931His	synonymous_variant	Exon 33 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.5814C>T	p.His1938His	synonymous_variant	Exon 32 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.5775C>T	p.His1925His	synonymous_variant	Exon 32 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5832C>T	p.His1944His	synonymous_variant	Exon 33 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5814C>T	p.His1938His	synonymous_variant	Exon 32 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5832C>T	p.His1944His	synonymous_variant	Exon 33 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5832C>T	p.His1944His	synonymous_variant	Exon 33 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.5832C>T	p.His1944His	synonymous_variant	Exon 33 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.5832C>T		non_coding_transcript_exon_variant	Exon 33 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1784C>T		non_coding_transcript_exon_variant	Exon 32 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*913C>T		non_coding_transcript_exon_variant	Exon 33 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*3683C>T		non_coding_transcript_exon_variant	Exon 33 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*5276C>T		non_coding_transcript_exon_variant	Exon 31 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*806C>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*691C>T		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1444C>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*499C>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*499C>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5814C>T		non_coding_transcript_exon_variant	Exon 32 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5832C>T		non_coding_transcript_exon_variant	Exon 33 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5832C>T		non_coding_transcript_exon_variant	Exon 33 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*948C>T		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*1784C>T		3_prime_UTR_variant	Exon 32 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*913C>T		3_prime_UTR_variant	Exon 33 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*3683C>T		3_prime_UTR_variant	Exon 33 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*5276C>T		3_prime_UTR_variant	Exon 31 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*806C>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*691C>T		3_prime_UTR_variant	Exon 33 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1444C>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*499C>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*499C>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518765.1
CACNA1H	ENST00000711488.1 link	n.*948C>T		3_prime_UTR_variant	Exon 33 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000673

AC:

117

AN:

173942

AF XY:

0.000674

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00109

Gnomad ASJ exome

AF:

0.00323

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000391

Gnomad OTH exome

AF:

0.00298

GnomAD4 exome

AF:

0.000254

AC:

359

AN:

1412594

Hom.:

Cov.:

AF XY:

0.000276

AC XY:

193

AN XY:

698046

show subpopulations

African (AFR)

AF:

0.0000308

AC:

AN:

32450

American (AMR)

AF:

0.000771

AC:

AN:

37592

Ashkenazi Jewish (ASJ)

AF:

0.00312

AC:

AN:

25296

East Asian (EAS)

AF:

0.00

AC:

AN:

37148

South Asian (SAS)

AF:

0.000548

AC:

AN:

80264

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48758

Middle Eastern (MID)

AF:

0.00649

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000121

AC:

132

AN:

1086834

Other (OTH)

AF:

0.000632

AC:

AN:

58554

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

107

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:

0.000368

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41512

American (AMR)

AF:

0.00190

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68002

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000737

Hom.:

Bravo

AF:

0.000450

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

CACNA1H-related disorder

Benign:1

Apr 03, 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). -

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

Benign:1

Feb 16, 2022

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

Jan 07, 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

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.17

(source)

DANN

Benign

0.62

PhyloP100

-0.27

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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