16-1208121-C-A

Variant names:

• chr16-1208121-C-A
• rs373190026
• NM_021098.3:c.3263C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021098.3(CACNA1H):​c.3263C>A​(p.Pro1088His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,441,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. P1088L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.30
• 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: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

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.3263C>A	p.Pro1088His	missense	Exon 16 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.3263C>A	p.Pro1088His	missense	Exon 16 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.3263C>A	p.Pro1088His	missense	Exon 16 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.3263C>A	p.Pro1088His	missense	Exon 16 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.3263C>A	p.Pro1088His	missense	Exon 16 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000462 AC: 1 AN: 216526 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000314

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1441804 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 715484

African (AFR) AF: 0.00 AC: 0 AN: 32888

American (AMR) AF: 0.0000470 AC: 2 AN: 42548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25746

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38324

South Asian (SAS) AF: 0.00 AC: 0 AN: 82696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5330

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103740

Other (OTH) AF: 0.00 AC: 0 AN: 59668

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000831 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.21		Gain of solvent accessibility (P = 0.0105)
MVP		0.91
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.57
gMVP		0.51
Mutation Taster		=84/16	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: rs373190026; hg19: chr16-1258121;