16-1204361-A-T

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.2354A>T(p.Lys785Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0038 in 1,576,242 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0029 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 21 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.97

Publications

11 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=0.03796467).

BP6

Variant 16-1204361-A-T is Benign according to our data. Variant chr16-1204361-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 460063.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00295 (449/152370) while in subpopulation AMR AF = 0.0049 (75/15312). AF 95% confidence interval is 0.00401. There are 2 homozygotes in GnomAd4. There are 211 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 449 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.2354A>T	p.Lys785Met	missense_variant	Exon 10 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.2354A>T	p.Lys785Met	missense_variant	Exon 10 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.2354A>T	p.Lys785Met	missense_variant	Exon 10 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.2354A>T	p.Lys785Met	missense_variant	Exon 10 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.2354A>T	p.Lys785Met	missense_variant	Exon 10 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.2354A>T	p.Lys785Met	missense_variant	Exon 10 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.2354A>T	p.Lys785Met	missense_variant	Exon 10 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.2315A>T	p.Lys772Met	missense_variant	Exon 10 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.2354A>T	p.Lys785Met	missense_variant	Exon 10 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.2315A>T	p.Lys772Met	missense_variant	Exon 10 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.2354A>T	p.Lys785Met	missense_variant	Exon 10 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.2354A>T	p.Lys785Met	missense_variant	Exon 10 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.2354A>T	p.Lys785Met	missense_variant	Exon 10 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.2354A>T	p.Lys785Met	missense_variant	Exon 10 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.2354A>T	p.Lys785Met	missense_variant	Exon 10 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.2354A>T		non_coding_transcript_exon_variant	Exon 10 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.2354A>T		non_coding_transcript_exon_variant	Exon 10 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.2354A>T		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*267A>T		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*1801A>T		non_coding_transcript_exon_variant	Exon 9 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.2354A>T		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.2354A>T		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.2354A>T		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.2354A>T		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.2354A>T		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.2354A>T		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.2354A>T		non_coding_transcript_exon_variant	Exon 10 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.2354A>T		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.2354A>T		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*267A>T		3_prime_UTR_variant	Exon 10 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*1801A>T		3_prime_UTR_variant	Exon 9 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.00295

AC:

449

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000506

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00497

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00423

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00419

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00357

AC:

774

AN:

216636

AF XY:

0.00362

show subpopulations

Gnomad AFR exome

AF:

0.000267

Gnomad AMR exome

AF:

0.00357

Gnomad ASJ exome

AF:

0.000862

Gnomad EAS exome

AF:

0.0000577

Gnomad FIN exome

AF:

0.00509

Gnomad NFE exome

AF:

0.00494

Gnomad OTH exome

AF:

0.00426

GnomAD4 exome

AF:

0.00389

AC:

5537

AN:

1423872

Hom.:

Cov.:

AF XY:

0.00397

AC XY:

2794

AN XY:

704212

show subpopulations

African (AFR)

AF:

0.000460

AC:

AN:

32584

American (AMR)

AF:

0.00385

AC:

155

AN:

40292

Ashkenazi Jewish (ASJ)

AF:

0.000851

AC:

AN:

23512

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39326

South Asian (SAS)

AF:

0.00210

AC:

167

AN:

79612

European-Finnish (FIN)

AF:

0.00498

AC:

251

AN:

50382

Middle Eastern (MID)

AF:

0.000896

AC:

AN:

5582

European-Non Finnish (NFE)

AF:

0.00427

AC:

4668

AN:

1093880

Other (OTH)

AF:

0.00434

AC:

255

AN:

58702

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

303

606

908

1211

1514

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

162

324

486

648

810

<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:

0.00295

AC:

449

AN:

152370

Hom.:

Cov.:

AF XY:

0.00283

AC XY:

211

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41588

American (AMR)

AF:

0.00490

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00290

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00423

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00419

AC:

285

AN:

68034

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

124

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:

0.00323

Hom.:

Bravo

AF:

0.00294

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000235

AC:

ESP6500EA

AF:

0.00331

AC:

ExAC

AF:

0.00358

AC:

430

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Feb 20, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 17, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35350424, 36786913)

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BS2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Benign:1

Jan 28, 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

0.31

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Uncertain

0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;.;.;.

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

T;T;T;.

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.038

T;T;T;T

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

3.2

M;.;M;M

PhyloP100

2.0

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.8

D;.;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.014

D;.;D;D

Sift4G

Uncertain

0.019

D;.;D;D

Vest4

0.72

ClinPred

0.029

GERP RS

3.9

Varity_R

0.11

gMVP

0.66

Mutation Taster

=100/0

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