NM_021098.3:c.2113C>T

Variant names:

• chr16-1204120-C-T
• rs56930579
• NM_021098.3:c.2113C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_021098.3(CACNA1H):​c.2113C>T​(p.Arg705Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,612,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R705L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.155
• Publications: 3 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28356794).
• BP6: Variant 16-1204120-C-T is Benign according to our data. Variant chr16-1204120-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 570351.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000118 (18/152352) while in subpopulation AMR AF = 0.000653 (10/15308). AF 95% confidence interval is 0.000354. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 18 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.2113C>T	p.Arg705Cys	missense	Exon 10 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.2113C>T	p.Arg705Cys	missense	Exon 10 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.2113C>T	p.Arg705Cys	missense	Exon 10 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.2113C>T	p.Arg705Cys	missense	Exon 10 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.2113C>T	p.Arg705Cys	missense	Exon 10 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000490 AC: 12 AN: 245026 AF XY: 0.0000597

Gnomad AFR exome AF: 0.0000669

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000560

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1459730 Hom.: 0 Cov.: 32 AF XY: 0.0000207 AC XY: 15 AN XY: 726112

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.000134 AC: 6 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000813 AC: 7 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111628

Other (OTH) AF: 0.0000497 AC: 3 AN: 60304

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74502

African (AFR) AF: 0.000168 AC: 7 AN: 41590

American (AMR) AF: 0.000653 AC: 10 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000387 Hom.: 0

Bravo AF: 0.000178

ExAC AF: 0.0000415 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.035	N
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.9	L
PhyloP100		0.15
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.29
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.13	T
Polyphen		0.97	D
Vest4		0.31
MVP		0.86
ClinPred		0.22	T
GERP RS		-1.2
Varity_R		0.14
gMVP		0.32
Mutation Taster		=96/4	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: rs56930579; hg19: chr16-1254120; COSMIC: COSV61992288; COSMIC: COSV61992288;