chr16-1153917-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_021098.3(CACNA1H):c.180G>C(p.Ala60Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00066 in 1,455,098 control chromosomes in the GnomAD database, including 2 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 0.00046 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00068 ( 2 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.0570

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 16-1153917-G-C is Benign according to our data. Variant chr16-1153917-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529649.

BP7

Synonymous conserved (PhyloP=0.057 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000455 (69/151490) while in subpopulation NFE AF = 0.00087 (59/67784). AF 95% confidence interval is 0.000692. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 69 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.180G>C	p.Ala60Ala	synonymous_variant	Exon 2 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.180G>C	p.Ala60Ala	synonymous_variant	Exon 2 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.180G>C	p.Ala60Ala	synonymous_variant	Exon 2 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.180G>C	p.Ala60Ala	synonymous_variant	Exon 2 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.180G>C	p.Ala60Ala	synonymous_variant	Exon 2 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.180G>C	p.Ala60Ala	synonymous_variant	Exon 2 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.180G>C	p.Ala60Ala	synonymous_variant	Exon 2 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.180G>C	p.Ala60Ala	synonymous_variant	Exon 2 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.180G>C	p.Ala60Ala	synonymous_variant	Exon 2 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.180G>C	p.Ala60Ala	synonymous_variant	Exon 2 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.180G>C	p.Ala60Ala	synonymous_variant	Exon 2 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.180G>C	p.Ala60Ala	synonymous_variant	Exon 2 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.180G>C	p.Ala60Ala	synonymous_variant	Exon 2 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.180G>C	p.Ala60Ala	synonymous_variant	Exon 2 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.180G>C	p.Ala60Ala	synonymous_variant	Exon 2 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.180G>C		non_coding_transcript_exon_variant	Exon 2 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.180G>C		non_coding_transcript_exon_variant	Exon 2 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.180G>C		non_coding_transcript_exon_variant	Exon 2 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.180G>C		non_coding_transcript_exon_variant	Exon 2 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.180G>C		non_coding_transcript_exon_variant	Exon 2 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.180G>C		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.180G>C		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.180G>C		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.180G>C		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.180G>C		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.180G>C		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.180G>C		non_coding_transcript_exon_variant	Exon 2 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.180G>C		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.180G>C		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.000455

AC:

AN:

151490

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000961

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000870

Gnomad OTH

AF:

0.000482

GnomAD2 exomes

AF:

0.000311

AC:

AN:

80370

AF XY:

0.000283

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000628

Gnomad ASJ exome

AF:

0.00121

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000172

Gnomad NFE exome

AF:

0.000523

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000683

AC:

891

AN:

1303608

Hom.:

Cov.:

AF XY:

0.000693

AC XY:

445

AN XY:

641838

show subpopulations

African (AFR)

AF:

0.0000378

AC:

AN:

26440

American (AMR)

AF:

0.000226

AC:

AN:

26532

Ashkenazi Jewish (ASJ)

AF:

0.000919

AC:

AN:

22844

East Asian (EAS)

AF:

0.00

AC:

AN:

27558

South Asian (SAS)

AF:

0.0000139

AC:

AN:

71948

European-Finnish (FIN)

AF:

0.000148

AC:

AN:

33772

Middle Eastern (MID)

AF:

0.000244

AC:

AN:

4106

European-Non Finnish (NFE)

AF:

0.000795

AC:

824

AN:

1036852

Other (OTH)

AF:

0.000598

AC:

AN:

53556

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

139

186

232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.000455

AC:

AN:

151490

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

AN XY:

73958

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41370

American (AMR)

AF:

0.00

AC:

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5118

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000961

AC:

AN:

10404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000870

AC:

AN:

67784

Other (OTH)

AF:

0.000482

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000788

Hom.:

Bravo

AF:

0.000450

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

-0.76

CADD

Benign

9.5

(source)

DANN

Benign

0.77

PhyloP100

0.057

PromoterAI

0.038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=99/1

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