NM_021098.3:c.2329C>T

Variant names:

• chr16-1204336-C-T
• rs375325893
• NM_021098.3:c.2329C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_021098.3(CACNA1H):​c.2329C>T​(p.Arg777Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,590,280 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. R777H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (2 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.14
• Publications: 4 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)
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2559896).
• BP6: Variant 16-1204336-C-T is Benign according to our data. Variant chr16-1204336-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 580279.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000139 (200/1437908) while in subpopulation MID AF = 0.0085 (48/5644). AF 95% confidence interval is 0.00659. There are 2 homozygotes in GnomAdExome4. There are 95 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 26 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.2329C>T	p.Arg777Cys	missense	Exon 10 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.2329C>T	p.Arg777Cys	missense	Exon 10 of 34	NP_001005407.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.2329C>T	p.Arg777Cys	missense	Exon 10 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.2329C>T	p.Arg777Cys	missense	Exon 10 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.2329C>T	p.Arg777Cys	missense	Exon 10 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000126 AC: 29 AN: 229254 AF XY: 0.000128

Gnomad AFR exome AF: 0.000271

Gnomad AMR exome AF: 0.0000934

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000495

Gnomad NFE exome AF: 0.000183

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.000139 AC: 200 AN: 1437908 Hom.: 2 Cov.: 32 AF XY: 0.000133 AC XY: 95 AN XY: 712246

African (AFR) AF: 0.000213 AC: 7 AN: 32896

American (AMR) AF: 0.0000944 AC: 4 AN: 42378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24816

East Asian (EAS) AF: 0.00 AC: 0 AN: 39304

South Asian (SAS) AF: 0.0000481 AC: 4 AN: 83242

European-Finnish (FIN) AF: 0.0000391 AC: 2 AN: 51194

Middle Eastern (MID) AF: 0.00850 AC: 48 AN: 5644

European-Non Finnish (NFE) AF: 0.000108 AC: 119 AN: 1099174

Other (OTH) AF: 0.000270 AC: 16 AN: 59260

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74520

African (AFR) AF: 0.000289 AC: 12 AN: 41586

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000143 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000100 AC: 12

ClinVar

ClinVar submissions as Germline

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.042	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.35
Sift	Benign	0.044	D
Sift4G	Benign	0.093	T
Polyphen		0.0040	B
Vest4		0.17
MVP		0.62
ClinPred		0.014	T
GERP RS		3.2
Varity_R		0.15
gMVP		0.42
Mutation Taster		=91/9	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: rs375325893; hg19: chr16-1254336; COSMIC: COSV61987339; COSMIC: COSV61987339;