NM_021098.3:c.1513C>T

Variant names:

• chr16-1201963-C-T
• rs60414549
• NM_021098.3:c.1513C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.1513C>T​(p.Arg505Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,544,942 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R505H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0063 (7 hom., cov: 34)
  • Exomes 𝑓: 0.00066 (9 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.32
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065402985).
• BP6: Variant 16-1201963-C-T is Benign according to our data. Variant chr16-1201963-C-T is described in ClinVar as Benign. ClinVar VariationId is 460049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0063 (960/152312) while in subpopulation AFR AF = 0.022 (913/41566). AF 95% confidence interval is 0.0208. There are 7 homozygotes in GnomAd4. There are 462 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 960 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.1513C>T	p.Arg505Cys	missense	Exon 9 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.1513C>T	p.Arg505Cys	missense	Exon 9 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.1513C>T	p.Arg505Cys	missense	Exon 9 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.1513C>T	p.Arg505Cys	missense	Exon 9 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.1513C>T	p.Arg505Cys	missense	Exon 9 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.00631 AC: 960 AN: 152194 Hom.: 7 Cov.: 34

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00141 AC: 200 AN: 141502 AF XY: 0.00102

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.000856

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000773

Gnomad OTH exome AF: 0.000718

GnomAD4 exome AF: 0.000665 AC: 926 AN: 1392630 Hom.: 9 Cov.: 36 AF XY: 0.000541 AC XY: 371 AN XY: 686266

African (AFR) AF: 0.0215 AC: 677 AN: 31484

American (AMR) AF: 0.00171 AC: 61 AN: 35584

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 29 AN: 25092

East Asian (EAS) AF: 0.00 AC: 0 AN: 35614

South Asian (SAS) AF: 0.000139 AC: 11 AN: 79114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45928

Middle Eastern (MID) AF: 0.00144 AC: 8 AN: 5558

European-Non Finnish (NFE) AF: 0.0000297 AC: 32 AN: 1076452

Other (OTH) AF: 0.00187 AC: 108 AN: 57804

GnomAD4 genome AF: 0.00630 AC: 960 AN: 152312 Hom.: 7 Cov.: 34 AF XY: 0.00620 AC XY: 462 AN XY: 74470

African (AFR) AF: 0.0220 AC: 913 AN: 41566

American (AMR) AF: 0.00157 AC: 24 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68010

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.000496 Hom.: 0

Bravo AF: 0.00701

ESP6500AA AF: 0.0135 AC: 48

ESP6500EA AF: 0.000141 AC: 1

ExAC AF: 0.000893 AC: 49

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	CACNA1H-related disorder (1)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0065	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.3
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.40
Sift	Benign	0.036	D
Sift4G	Uncertain	0.047	D
Polyphen		1.0	D
Vest4		0.34
MVP		0.88
ClinPred		0.019	T
GERP RS		-0.56
Varity_R		0.081
gMVP		0.44
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs60414549; hg19: chr16-1251963; COSMIC: COSV107431089; COSMIC: COSV107431089;