16-1204369-C-T

Variant names:

• chr16-1204369-C-T
• rs3751664
• NM_021098.3:c.2362C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021098.3(CACNA1H):​c.2362C>T​(p.Arg788Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0917 in 1,570,246 control chromosomes in the GnomAD database, including 7,457 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. R788G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.074 (591 hom., cov: 33)
  • Exomes 𝑓: 0.094 (6866 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.252
• Publications: 43 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00224787).
• BP6: Variant 16-1204369-C-T is Benign according to our data. Variant chr16-1204369-C-T is described in ClinVar as Benign. ClinVar VariationId is 96008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

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.2362C>T	p.Arg788Cys	missense	Exon 10 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.2362C>T	p.Arg788Cys	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.2362C>T	p.Arg788Cys	missense	Exon 10 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.2362C>T	p.Arg788Cys	missense	Exon 10 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.2362C>T	p.Arg788Cys	missense	Exon 10 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.0738 AC: 11231 AN: 152166 Hom.: 591 Cov.: 33

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.0550

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0885

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.0712

GnomAD2 exomes AF: 0.0815 AC: 17344 AN: 212698 AF XY: 0.0818

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.0364

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.104

Gnomad FIN exome AF: 0.0915

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.0934

GnomAD4 exome AF: 0.0936 AC: 132694 AN: 1417962 Hom.: 6866 Cov.: 33 AF XY: 0.0922 AC XY: 64585 AN XY: 700602

African (AFR) AF: 0.0143 AC: 465 AN: 32506

American (AMR) AF: 0.0386 AC: 1533 AN: 39698

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 2909 AN: 23006

East Asian (EAS) AF: 0.123 AC: 4836 AN: 39304

South Asian (SAS) AF: 0.0209 AC: 1638 AN: 78216

European-Finnish (FIN) AF: 0.0997 AC: 4991 AN: 50038

Middle Eastern (MID) AF: 0.0420 AC: 233 AN: 5554

European-Non Finnish (NFE) AF: 0.102 AC: 111025 AN: 1091162

Other (OTH) AF: 0.0866 AC: 5064 AN: 58478

GnomAD4 genome AF: 0.0737 AC: 11230 AN: 152284 Hom.: 591 Cov.: 33 AF XY: 0.0699 AC XY: 5203 AN XY: 74448

African (AFR) AF: 0.0153 AC: 635 AN: 41588

American (AMR) AF: 0.0548 AC: 839 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 439 AN: 3470

East Asian (EAS) AF: 0.105 AC: 544 AN: 5162

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4828

European-Finnish (FIN) AF: 0.0885 AC: 939 AN: 10612

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7394 AN: 68006

Other (OTH) AF: 0.0700 AC: 148 AN: 2114

Alfa AF: 0.0965 Hom.: 853

Bravo AF: 0.0694

TwinsUK AF: 0.106 AC: 393

ALSPAC AF: 0.100 AC: 386

ESP6500AA AF: 0.0154 AC: 66

ESP6500EA AF: 0.103 AC: 876

ExAC AF: 0.0821 AC: 9851

Asia WGS AF: 0.0720 AC: 250 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	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	-0.27	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.058	N
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.25
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.36
Sift	Benign	0.033	D
Sift4G	Uncertain	0.039	D
Polyphen		0.018	B
Vest4		0.28
ClinPred		0.033	T
GERP RS		0.51
Varity_R		0.21
gMVP		0.54
Mutation Taster		=98/2	polymorphism (auto)

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: rs3751664; hg19: chr16-1254369; COSMIC: COSV61983678; COSMIC: COSV61983678;