rs56930660

Variant names:

• chr16-1220254-G-A
• rs56930660
• NM_021098.3:c.6322G>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.6322G>A​(p.Ala2108Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,583,922 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2108V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 35)
  • Exomes 𝑓: 0.0019 (7 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.77
• Publications: 4 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: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.03981313).
• BP6: Variant 16-1220254-G-A is Benign according to our data. Variant chr16-1220254-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 460163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00123 (187/152212) while in subpopulation NFE AF = 0.00204 (139/68000). AF 95% confidence interval is 0.00177. There are 1 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High AC in GnomAd4 at 187 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.6322G>A	p.Ala2108Thr	missense	Exon 35 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.6304G>A	p.Ala2102Thr	missense	Exon 34 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.6322G>A	p.Ala2108Thr	missense	Exon 35 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.6337G>A	p.Ala2113Thr	missense	Exon 34 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.6307G>A	p.Ala2103Thr	missense	Exon 34 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 188 AN: 152098 Hom.: 1 Cov.: 35

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000591

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00145 AC: 301 AN: 208054 AF XY: 0.00148

Gnomad AFR exome AF: 0.000285

Gnomad AMR exome AF: 0.000555

Gnomad ASJ exome AF: 0.00125

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000489

Gnomad NFE exome AF: 0.00234

Gnomad OTH exome AF: 0.00154

GnomAD4 exome AF: 0.00193 AC: 2760 AN: 1431710 Hom.: 7 Cov.: 73 AF XY: 0.00193 AC XY: 1377 AN XY: 711966

African (AFR) AF: 0.000352 AC: 11 AN: 31264

American (AMR) AF: 0.000464 AC: 20 AN: 43086

Ashkenazi Jewish (ASJ) AF: 0.00114 AC: 29 AN: 25368

East Asian (EAS) AF: 0.0000264 AC: 1 AN: 37860

South Asian (SAS) AF: 0.000890 AC: 75 AN: 84306

European-Finnish (FIN) AF: 0.000757 AC: 31 AN: 40970

Middle Eastern (MID) AF: 0.00123 AC: 7 AN: 5676

European-Non Finnish (NFE) AF: 0.00226 AC: 2497 AN: 1103814

Other (OTH) AF: 0.00150 AC: 89 AN: 59366

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152212 Hom.: 1 Cov.: 35 AF XY: 0.00114 AC XY: 85 AN XY: 74416

African (AFR) AF: 0.000529 AC: 22 AN: 41566

American (AMR) AF: 0.000591 AC: 9 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10626

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00204 AC: 139 AN: 68000

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00151 Hom.: 0

Bravo AF: 0.00122

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00169 AC: 12

ExAC AF: 0.00128 AC: 149

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	CACNA1H-related disorder (1)
-	-	1	Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV (1)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.040	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.59	N
REVEL	Uncertain	0.31
Sift	Benign	0.31	T
Sift4G	Benign	0.61	T
Polyphen		0.99	D
Vest4		0.076
MVP		0.93
ClinPred		0.022	T
GERP RS		4.3
Varity_R		0.057
gMVP		0.24
Mutation Taster		=98/2	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: rs56930660; hg19: chr16-1270254;