chr16-1211495-G-A

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.4365G>A(p.Lys1455Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000054 in 1,612,484 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.93

Publications

0 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=-0.55).

BP6

Variant 16-1211495-G-A is Benign according to our data. Variant chr16-1211495-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 460114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.93 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000555 (81/1460166) while in subpopulation MID AF = 0.00191 (11/5768). AF 95% confidence interval is 0.00107. There are 1 homozygotes in GnomAdExome4. There are 37 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4365G>A	p.Lys1455Lys	synonymous_variant	Exon 23 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.4365G>A	p.Lys1455Lys	synonymous_variant	Exon 23 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4365G>A	p.Lys1455Lys	synonymous_variant	Exon 23 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4401G>A	p.Lys1467Lys	synonymous_variant	Exon 23 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4365G>A	p.Lys1455Lys	synonymous_variant	Exon 23 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4365G>A	p.Lys1455Lys	synonymous_variant	Exon 23 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4365G>A	p.Lys1455Lys	synonymous_variant	Exon 23 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4326G>A	p.Lys1442Lys	synonymous_variant	Exon 23 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4365G>A	p.Lys1455Lys	synonymous_variant	Exon 23 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4326G>A	p.Lys1442Lys	synonymous_variant	Exon 23 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4365G>A	p.Lys1455Lys	synonymous_variant	Exon 23 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4365G>A	p.Lys1455Lys	synonymous_variant	Exon 23 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4365G>A	p.Lys1455Lys	synonymous_variant	Exon 23 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4365G>A	p.Lys1455Lys	synonymous_variant	Exon 23 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4365G>A	p.Lys1455Lys	synonymous_variant	Exon 23 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4365G>A		non_coding_transcript_exon_variant	Exon 23 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*335G>A		non_coding_transcript_exon_variant	Exon 23 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4365G>A		non_coding_transcript_exon_variant	Exon 23 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2278G>A		non_coding_transcript_exon_variant	Exon 23 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3812G>A		non_coding_transcript_exon_variant	Exon 22 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4365G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4365G>A		non_coding_transcript_exon_variant	Exon 23 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4365G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4365G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4365G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4365G>A		non_coding_transcript_exon_variant	Exon 23 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4365G>A		non_coding_transcript_exon_variant	Exon 23 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4365G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4365G>A		non_coding_transcript_exon_variant	Exon 23 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*335G>A		3_prime_UTR_variant	Exon 23 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2278G>A		3_prime_UTR_variant	Exon 23 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3812G>A		3_prime_UTR_variant	Exon 22 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000109

AC:

AN:

247684

AF XY:

0.0000964

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000895

Gnomad OTH exome

AF:

0.000664

GnomAD4 exome

AF:

0.0000555

AC:

AN:

1460166

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

726374

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33468

American (AMR)

AF:

0.0000224

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000220

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52118

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

1111690

Other (OTH)

AF:

0.000182

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

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:

0.0000394

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.000113

Hom.:

Bravo

AF:

0.0000302

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

May 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

5.9

(source)

DANN

Benign

0.78

PhyloP100

1.9

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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