chr16-1213792-G-C

Variant names:

• chr16-1213792-G-C
• rs370079169
• NM_021098.3:c.4790G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_021098.3(CACNA1H):​c.4790G>C​(p.Arg1597Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 1,411,470 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1597W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• 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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 19 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.4790G>C	p.Arg1597Pro	missense	Exon 27 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.4772G>C	p.Arg1591Pro	missense	Exon 26 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.4790G>C	p.Arg1597Pro	missense	Exon 27 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.4805G>C	p.Arg1602Pro	missense	Exon 26 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.4808G>C	p.Arg1603Pro	missense	Exon 26 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000115 AC: 2 AN: 173394 AF XY: 0.0000107

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000713

Gnomad NFE exome AF: 0.0000137

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000135 AC: 19 AN: 1411470 Hom.: 0 Cov.: 31 AF XY: 0.0000115 AC XY: 8 AN XY: 698010

African (AFR) AF: 0.00 AC: 0 AN: 32370

American (AMR) AF: 0.00 AC: 0 AN: 37114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25366

East Asian (EAS) AF: 0.00 AC: 0 AN: 37066

South Asian (SAS) AF: 0.00 AC: 0 AN: 80776

European-Finnish (FIN) AF: 0.0000220 AC: 1 AN: 45542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.0000156 AC: 17 AN: 1088816

Other (OTH) AF: 0.0000170 AC: 1 AN: 58736

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000339 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	0.061
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Pathogenic	0.97	D
PhyloP100		1.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.57
Sift	Benign	0.26	T
Sift4G	Benign	0.22	T
Polyphen		0.97	D
Vest4		0.69
MutPred		0.47		Gain of catalytic residue at R1597 (P = 0.0143)
MVP		0.93
ClinPred		0.93	D
GERP RS		3.9
Varity_R		0.70
gMVP		0.81
Mutation Taster		=65/35	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: rs370079169; hg19: chr16-1263792;