chr16-1210082-G-C

Variant names:

• chr16-1210082-G-C
• rs200228767
• NM_021098.3:c.3792G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021098.3(CACNA1H):​c.3792G>C​(p.Gln1264His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,407,528 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.408
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.3792G>C	p.Gln1264His	missense	Exon 18 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.3792G>C	p.Gln1264His	missense	Exon 18 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.3792G>C	p.Gln1264His	missense	Exon 18 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.3792G>C	p.Gln1264His	missense	Exon 18 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.3792G>C	p.Gln1264His	missense	Exon 18 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000284 AC: 4 AN: 1407528 Hom.: 0 Cov.: 34 AF XY: 0.00000431 AC XY: 3 AN XY: 695280

African (AFR) AF: 0.00 AC: 0 AN: 31840

American (AMR) AF: 0.00 AC: 0 AN: 37374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25276

East Asian (EAS) AF: 0.00 AC: 0 AN: 36264

South Asian (SAS) AF: 0.00 AC: 0 AN: 79656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000369 AC: 4 AN: 1084696

Other (OTH) AF: 0.00 AC: 0 AN: 58364

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.41
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.68
Sift	Benign	0.11	T
Sift4G	Benign	0.10	T
Polyphen		0.61	P
Vest4		0.20
MutPred		0.77		Gain of helix (P = 0.0325)
MVP		0.98
ClinPred		0.73	D
GERP RS		1.7
PromoterAI		-0.016	Neutral
Varity_R		0.12
gMVP		0.71
Mutation Taster		=82/18	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: rs200228767; hg19: chr16-1260082;