NM_021098.3:c.2842G>A

Variant names:

• chr16-1207053-G-A
• rs763407611
• NM_021098.3:c.2842G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_021098.3(CACNA1H):​c.2842G>A​(p.Gly948Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,602,864 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.95
• 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)

ENSG00000261294 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• BS2: High AC in GnomAd4 at 7 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.2842G>A	p.Gly948Arg	missense	Exon 13 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.2842G>A	p.Gly948Arg	missense	Exon 13 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.2842G>A	p.Gly948Arg	missense	Exon 13 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.2842G>A	p.Gly948Arg	missense	Exon 13 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.2842G>A	p.Gly948Arg	missense	Exon 13 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151862 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000473 AC: 11 AN: 232658 AF XY: 0.0000238

Gnomad AFR exome AF: 0.000218

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000488

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1450884 Hom.: 0 Cov.: 32 AF XY: 0.0000167 AC XY: 12 AN XY: 720618

African (AFR) AF: 0.000240 AC: 8 AN: 33280

American (AMR) AF: 0.0000919 AC: 4 AN: 43514

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39246

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84276

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 51992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1106966

Other (OTH) AF: 0.0000334 AC: 2 AN: 59942

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151980 Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2 AN XY: 74282

African (AFR) AF: 0.000145 AC: 6 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67944

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000414 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV (1)
-	1	-	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.82
Sift	Benign	0.031	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.48		Gain of glycosylation at T947 (P = 0.0415)
MVP		0.95
ClinPred		0.98	D
GERP RS		3.3
Varity_R		0.79
gMVP		0.87
Mutation Taster		=48/52	disease causing

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: rs763407611; hg19: chr16-1257053; COSMIC: COSV61995482; COSMIC: COSV61995482;