rs1045818263

Variant names:

• chr16-1195483-A-T
• rs1045818263
• NM_021098.3:c.463A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_021098.3(CACNA1H):​c.463A>T​(p.Met155Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000214 in 1,589,898 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. M155I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.23
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0959402).
• BS2: High AC in GnomAd4 at 31 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.463A>T	p.Met155Leu	missense	Exon 4 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.463A>T	p.Met155Leu	missense	Exon 4 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.463A>T	p.Met155Leu	missense	Exon 4 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.463A>T	p.Met155Leu	missense	Exon 4 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.463A>T	p.Met155Leu	missense	Exon 4 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 151986 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1437912 Hom.: 0 Cov.: 34 AF XY: 0.00000281 AC XY: 2 AN XY: 712760

African (AFR) AF: 0.00 AC: 0 AN: 33036

American (AMR) AF: 0.00 AC: 0 AN: 40954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25658

East Asian (EAS) AF: 0.00 AC: 0 AN: 38620

South Asian (SAS) AF: 0.00 AC: 0 AN: 82296

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1100130

Other (OTH) AF: 0.00 AC: 0 AN: 59586

GnomAD4 genome AF: 0.000204 AC: 31 AN: 151986 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74228

African (AFR) AF: 0.00 AC: 0 AN: 41364

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000257

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	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.096	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.69
Sift	Benign	0.11	T
Sift4G	Uncertain	0.010	D
Polyphen		0.95	P
Vest4		0.73
MutPred		0.58		Gain of methylation at K154 (P = 0.0678)
MVP		0.90
ClinPred		0.98	D
GERP RS		3.7
Varity_R		0.46
gMVP		0.72
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1045818263; hg19: chr16-1245483;