chr16-1218439-G-T

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.5675G>T(p.Arg1892Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,552,680 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1892H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0057 ( 12 hom., cov: 34)

Exomes 𝑓: 0.00052 ( 3 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.683

Publications

8 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=0.005491793).

BP6

Variant 16-1218439-G-T is Benign according to our data. Variant chr16-1218439-G-T is described in ClinVar as [Benign]. Clinvar id is 460151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00566 (862/152308) while in subpopulation AFR AF = 0.0193 (804/41556). AF 95% confidence interval is 0.0182. There are 12 homozygotes in GnomAd4. There are 403 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 862 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5675G>T	p.Arg1892Leu	missense_variant	Exon 33 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.5675G>T	p.Arg1892Leu	missense_variant	Exon 33 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.5690G>T	p.Arg1897Leu	missense_variant	Exon 32 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.5693G>T	p.Arg1898Leu	missense_variant	Exon 32 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5657G>T	p.Arg1886Leu	missense_variant	Exon 32 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.5690G>T	p.Arg1897Leu	missense_variant	Exon 33 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5675G>T	p.Arg1892Leu	missense_variant	Exon 33 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.5636G>T	p.Arg1879Leu	missense_variant	Exon 33 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.5657G>T	p.Arg1886Leu	missense_variant	Exon 32 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.5618G>T	p.Arg1873Leu	missense_variant	Exon 32 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5675G>T	p.Arg1892Leu	missense_variant	Exon 33 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5657G>T	p.Arg1886Leu	missense_variant	Exon 32 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5675G>T	p.Arg1892Leu	missense_variant	Exon 33 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5675G>T	p.Arg1892Leu	missense_variant	Exon 33 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.5675G>T	p.Arg1892Leu	missense_variant	Exon 33 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.5675G>T		non_coding_transcript_exon_variant	Exon 33 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1627G>T		non_coding_transcript_exon_variant	Exon 32 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*756G>T		non_coding_transcript_exon_variant	Exon 33 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3526G>T		non_coding_transcript_exon_variant	Exon 33 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*5119G>T		non_coding_transcript_exon_variant	Exon 31 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*649G>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*534G>T		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1287G>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*342G>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*342G>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5657G>T		non_coding_transcript_exon_variant	Exon 32 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5675G>T		non_coding_transcript_exon_variant	Exon 33 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5675G>T		non_coding_transcript_exon_variant	Exon 33 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*791G>T		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*1627G>T		3_prime_UTR_variant	Exon 32 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*756G>T		3_prime_UTR_variant	Exon 33 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3526G>T		3_prime_UTR_variant	Exon 33 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*5119G>T		3_prime_UTR_variant	Exon 31 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*649G>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*534G>T		3_prime_UTR_variant	Exon 33 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1287G>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*342G>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*342G>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518765.1
CACNA1H	ENST00000711488.1 link	n.*791G>T		3_prime_UTR_variant	Exon 33 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.00565

AC:

860

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00307

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00121

AC:

191

AN:

158130

AF XY:

0.000835

show subpopulations

Gnomad AFR exome

AF:

0.0199

Gnomad AMR exome

AF:

0.000965

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000160

Gnomad OTH exome

AF:

0.00112

GnomAD4 exome

AF:

0.000518

AC:

725

AN:

1400372

Hom.:

Cov.:

AF XY:

0.000447

AC XY:

309

AN XY:

690952

show subpopulations

African (AFR)

AF:

0.0181

AC:

574

AN:

31698

American (AMR)

AF:

0.00120

AC:

AN:

35938

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25190

East Asian (EAS)

AF:

0.00

AC:

AN:

35852

South Asian (SAS)

AF:

0.0000378

AC:

AN:

79348

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47854

Middle Eastern (MID)

AF:

0.00106

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.0000130

AC:

AN:

1080634

Other (OTH)

AF:

0.00146

AC:

AN:

58192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00566

AC:

862

AN:

152308

Hom.:

Cov.:

AF XY:

0.00541

AC XY:

403

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0193

AC:

804

AN:

41556

American (AMR)

AF:

0.00307

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68024

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

130

173

216

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:

0.00148

Hom.:

Bravo

AF:

0.00651

ESP6500AA

AF:

0.0124

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.000875

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 25, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Jan 08, 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

0.084

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

2.1

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.11

T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.65

T;T;T;.

MetaRNN

Benign

0.0055

T;T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

0.0

N;.;.;.

PhyloP100

-0.68

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.54

N;.;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.33

T;.;T;T

Sift4G

Benign

0.30

T;.;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.12

MVP

0.66

ClinPred

0.0026

GERP RS

-0.61

Varity_R

0.10

gMVP

0.39

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