rs758461760

Variant names:

• chr16-1220140-C-G
• rs758461760
• NM_021098.3:c.6208C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-1220140-C-G
• chr16-1220140-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021098.3(CACNA1H):​c.6208C>G​(p.Arg2070Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,354,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2070H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3128326).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.6208C>G	p.Arg2070Gly	missense	Exon 35 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.6190C>G	p.Arg2064Gly	missense	Exon 34 of 34	NP_001005407.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.6208C>G	p.Arg2070Gly	missense	Exon 35 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.6223C>G	p.Arg2075Gly	missense	Exon 34 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.6193C>G	p.Arg2065Gly	missense	Exon 34 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1354178 Hom.: 0 Cov.: 31 AF XY: 0.00000150 AC XY: 1 AN XY: 664592

African (AFR) AF: 0.00 AC: 0 AN: 27714

American (AMR) AF: 0.00 AC: 0 AN: 31366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20778

East Asian (EAS) AF: 0.00 AC: 0 AN: 34478

South Asian (SAS) AF: 0.0000145 AC: 1 AN: 68776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5350

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1061100

Other (OTH) AF: 0.00 AC: 0 AN: 55732

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.021	D
Sift4G	Benign	0.20	T
Polyphen		0.79	P
Vest4		0.29
MutPred		0.24		Loss of methylation at R2070 (P = 0.0137)
MVP		0.90
ClinPred		0.94	D
GERP RS		4.6
Varity_R		0.40
gMVP		0.29
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs758461760; hg19: chr16-1270140;