rs187596702

Variant names:

• chr16-1195057-G-A
• rs187596702
• NM_021098.3:c.385G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.385G>A​(p.Gly129Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,608,740 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G129G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.369
• Publications: 1 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022167772).
• BP6: Variant 16-1195057-G-A is Benign according to our data. Variant chr16-1195057-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460098.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 = 0.000982 (149/151674) while in subpopulation AFR AF = 0.00327 (135/41310). AF 95% confidence interval is 0.00282. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 149 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.385G>A	p.Gly129Ser	missense_variant	Exon 3 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.385G>A	p.Gly129Ser	missense_variant	Exon 3 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.385G>A	p.Gly129Ser	missense_variant	Exon 3 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.385G>A	p.Gly129Ser	missense_variant	Exon 3 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.385G>A	p.Gly129Ser	missense_variant	Exon 3 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.385G>A	p.Gly129Ser	missense_variant	Exon 3 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.385G>A	p.Gly129Ser	missense_variant	Exon 3 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.385G>A	p.Gly129Ser	missense_variant	Exon 3 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.385G>A	p.Gly129Ser	missense_variant	Exon 3 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.385G>A	p.Gly129Ser	missense_variant	Exon 3 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.385G>A	p.Gly129Ser	missense_variant	Exon 3 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.385G>A	p.Gly129Ser	missense_variant	Exon 3 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.385G>A	p.Gly129Ser	missense_variant	Exon 3 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.385G>A	p.Gly129Ser	missense_variant	Exon 3 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.385G>A	p.Gly129Ser	missense_variant	Exon 3 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.385G>A		non_coding_transcript_exon_variant	Exon 3 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.385G>A		non_coding_transcript_exon_variant	Exon 3 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.385G>A		non_coding_transcript_exon_variant	Exon 3 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.385G>A		non_coding_transcript_exon_variant	Exon 3 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.385G>A		non_coding_transcript_exon_variant	Exon 3 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.385G>A		non_coding_transcript_exon_variant	Exon 3 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.385G>A		non_coding_transcript_exon_variant	Exon 3 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.385G>A		non_coding_transcript_exon_variant	Exon 3 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.385G>A		non_coding_transcript_exon_variant	Exon 3 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.385G>A		non_coding_transcript_exon_variant	Exon 3 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.385G>A		non_coding_transcript_exon_variant	Exon 3 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.385G>A		non_coding_transcript_exon_variant	Exon 3 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.385G>A		non_coding_transcript_exon_variant	Exon 3 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.385G>A		non_coding_transcript_exon_variant	Exon 3 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes AF: 0.000977 AC: 148 AN: 151558 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000789

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: 0.00

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.000254 AC: 63 AN: 247930 AF XY: 0.000185

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000132 AC: 193 AN: 1457066 Hom.: 1 Cov.: 32 AF XY: 0.000119 AC XY: 86 AN XY: 724158

African (AFR) AF: 0.00437 AC: 146 AN: 33408

American (AMR) AF: 0.000246 AC: 11 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000902 AC: 10 AN: 1109094

Other (OTH) AF: 0.000382 AC: 23 AN: 60154

GnomAD4 genome AF: 0.000982 AC: 149 AN: 151674 Hom.: 0 Cov.: 29 AF XY: 0.000890 AC XY: 66 AN XY: 74134

African (AFR) AF: 0.00327 AC: 135 AN: 41310

American (AMR) AF: 0.000788 AC: 12 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67902

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.0263 Hom.: 2342

Bravo AF: 0.00137

ESP6500AA AF: 0.00357 AC: 15

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000256 AC: 31

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CACNA1H-related disorder Benign:1

Jul 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Sep 07, 2017

Athena Diagnostics

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	0.075
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.34	T;.;.;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T;T;T;.
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.022	T;T;T;T
MetaSVM	Uncertain	0.034	D
MutationAssessor	Benign	0.0	N;.;N;N
PhyloP100		0.37
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.87	N;.;N;N
REVEL	Benign	0.29
Sift	Benign	0.71	T;.;T;T
Sift4G	Benign	0.73	T;.;T;T
Polyphen		0.12	B;.;P;P
Vest4		0.26
MVP		0.63
ClinPred		0.0084	T
GERP RS		3.5
Varity_R		0.029
gMVP		0.25
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs187596702; hg19: chr16-1245057;