16-1218494-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_021098.3(CACNA1H):c.5730C>T(p.Asp1910Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 1,552,098 control chromosomes in the GnomAD database, including 291,865 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 32402 hom., cov: 32)

Exomes 𝑓: 0.61 ( 259463 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.43

Publications

24 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=-0.72).

BP6

Variant 16-1218494-C-T is Benign according to our data. Variant chr16-1218494-C-T is described in ClinVar as Benign. ClinVar VariationId is 585653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.43 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5730C>T	p.Asp1910Asp	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.5730C>T	p.Asp1910Asp	synonymous_variant	Exon 33 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.5745C>T	p.Asp1915Asp	synonymous_variant	Exon 32 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.5748C>T	p.Asp1916Asp	synonymous_variant	Exon 32 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5712C>T	p.Asp1904Asp	synonymous_variant	Exon 32 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.5745C>T	p.Asp1915Asp	synonymous_variant	Exon 33 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5730C>T	p.Asp1910Asp	synonymous_variant	Exon 33 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.5691C>T	p.Asp1897Asp	synonymous_variant	Exon 33 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.5712C>T	p.Asp1904Asp	synonymous_variant	Exon 32 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.5673C>T	p.Asp1891Asp	synonymous_variant	Exon 32 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5730C>T	p.Asp1910Asp	synonymous_variant	Exon 33 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5712C>T	p.Asp1904Asp	synonymous_variant	Exon 32 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5730C>T	p.Asp1910Asp	synonymous_variant	Exon 33 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5730C>T	p.Asp1910Asp	synonymous_variant	Exon 33 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.5730C>T	p.Asp1910Asp	synonymous_variant	Exon 33 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.5730C>T		non_coding_transcript_exon_variant	Exon 33 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1682C>T		non_coding_transcript_exon_variant	Exon 32 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*811C>T		non_coding_transcript_exon_variant	Exon 33 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*3581C>T		non_coding_transcript_exon_variant	Exon 33 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*5174C>T		non_coding_transcript_exon_variant	Exon 31 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*704C>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*589C>T		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1342C>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*397C>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*397C>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5712C>T		non_coding_transcript_exon_variant	Exon 32 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5730C>T		non_coding_transcript_exon_variant	Exon 33 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5730C>T		non_coding_transcript_exon_variant	Exon 33 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*846C>T		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*1682C>T		3_prime_UTR_variant	Exon 32 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*811C>T		3_prime_UTR_variant	Exon 33 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*3581C>T		3_prime_UTR_variant	Exon 33 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*5174C>T		3_prime_UTR_variant	Exon 31 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*704C>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*589C>T		3_prime_UTR_variant	Exon 33 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1342C>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*397C>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*397C>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518765.1
CACNA1H	ENST00000711488.1 link	n.*846C>T		3_prime_UTR_variant	Exon 33 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.648

AC:

98414

AN:

151874

Hom.:

32373

Cov.:

show subpopulations

Gnomad AFR

AF:

0.691

Gnomad AMI

AF:

0.573

Gnomad AMR

AF:

0.701

Gnomad ASJ

AF:

0.712

Gnomad EAS

AF:

0.876

Gnomad SAS

AF:

0.565

Gnomad FIN

AF:

0.710

Gnomad MID

AF:

0.706

Gnomad NFE

AF:

0.587

Gnomad OTH

AF:

0.652

GnomAD2 exomes

AF:

0.653

AC:

102817

AN:

157464

AF XY:

0.641

show subpopulations

Gnomad AFR exome

AF:

0.697

Gnomad AMR exome

AF:

0.737

Gnomad ASJ exome

AF:

0.693

Gnomad EAS exome

AF:

0.887

Gnomad FIN exome

AF:

0.697

Gnomad NFE exome

AF:

0.592

Gnomad OTH exome

AF:

0.642

GnomAD4 exome

AF:

0.605

AC:

847097

AN:

1400106

Hom.:

259463

Cov.:

AF XY:

0.603

AC XY:

416553

AN XY:

690898

show subpopulations

African (AFR)

AF:

0.698

AC:

22131

AN:

31710

American (AMR)

AF:

0.729

AC:

26223

AN:

35970

Ashkenazi Jewish (ASJ)

AF:

0.695

AC:

17504

AN:

25194

East Asian (EAS)

AF:

0.901

AC:

32329

AN:

35896

South Asian (SAS)

AF:

0.561

AC:

44563

AN:

79372

European-Finnish (FIN)

AF:

0.690

AC:

33073

AN:

47946

Middle Eastern (MID)

AF:

0.701

AC:

3991

AN:

5694

European-Non Finnish (NFE)

AF:

0.584

AC:

630843

AN:

1080218

Other (OTH)

AF:

0.627

AC:

36440

AN:

58106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

21129

42257

63386

84514

105643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17692

35384

53076

70768

88460

<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:

0.648

AC:

98490

AN:

151992

Hom.:

32402

Cov.:

AF XY:

0.655

AC XY:

48670

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.690

AC:

28611

AN:

41444

American (AMR)

AF:

0.701

AC:

10714

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.712

AC:

2473

AN:

3472

East Asian (EAS)

AF:

0.876

AC:

4485

AN:

5122

South Asian (SAS)

AF:

0.564

AC:

2717

AN:

4818

European-Finnish (FIN)

AF:

0.710

AC:

7521

AN:

10596

Middle Eastern (MID)

AF:

0.697

AC:

205

AN:

294

European-Non Finnish (NFE)

AF:

0.587

AC:

39855

AN:

67942

Other (OTH)

AF:

0.657

AC:

1388

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1750

3500

5249

6999

8749

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

794

1588

2382

3176

3970

<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:

0.614

Hom.:

16244

Bravo

AF:

0.657

Asia WGS

AF:

0.723

AC:

2513

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 27, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 04, 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

-0.72

CADD

Benign

0.70

(source)

DANN

Benign

0.68

PhyloP100

-2.4

Mutation Taster

=100/0

polymorphism (auto)

(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