chr16-1198704-G-A

Variant names:

• chr16-1198704-G-A
• rs774687054
• NM_021098.3:c.733G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3 BP6_Moderate BS2

The NM_021098.3(CACNA1H):​c.733G>A​(p.Gly245Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.43
• 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: Likely_benign. The variant received -5 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 16-1198704-G-A is Benign according to our data. Variant chr16-1198704-G-A is described in ClinVar as Benign. ClinVar VariationId is 460186.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 10 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.733G>A	p.Gly245Ser	missense	Exon 6 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.733G>A	p.Gly245Ser	missense	Exon 6 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.733G>A	p.Gly245Ser	missense	Exon 6 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.733G>A	p.Gly245Ser	missense	Exon 6 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.733G>A	p.Gly245Ser	missense	Exon 6 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248804 AF XY: 0.00000740

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461160 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726886

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111660

Other (OTH) AF: 0.0000166 AC: 1 AN: 60344

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.2	L
PhyloP100		7.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.77
Sift	Benign	0.074	T
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.68		Gain of glycosylation at G245 (P = 0.1323)
MVP		0.96
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.73
gMVP		0.96
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.58		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs774687054; hg19: chr16-1248704;