rs756154211

Variant names:

• chr16-1209311-C-T
• rs756154211
• NM_021098.3:c.3643C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_021098.3(CACNA1H):​c.3643C>T​(p.Arg1215Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,596,574 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R1215H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000051 (1 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.83
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38686275).
• BP6: Variant 16-1209311-C-T is Benign according to our data. Variant chr16-1209311-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529594.
• BS2: High AC in GnomAd4 at 14 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.3643C>T	p.Arg1215Cys	missense	Exon 17 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.3643C>T	p.Arg1215Cys	missense	Exon 17 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.3643C>T	p.Arg1215Cys	missense	Exon 17 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.3643C>T	p.Arg1215Cys	missense	Exon 17 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.3643C>T	p.Arg1215Cys	missense	Exon 17 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000535 AC: 12 AN: 224194 AF XY: 0.0000481

Gnomad AFR exome AF: 0.000151

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000487

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000512 AC: 74 AN: 1444252 Hom.: 1 Cov.: 31 AF XY: 0.0000570 AC XY: 41 AN XY: 718812

African (AFR) AF: 0.000120 AC: 4 AN: 33400

American (AMR) AF: 0.000180 AC: 8 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39502

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1110488

Other (OTH) AF: 0.0000832 AC: 5 AN: 60076

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74482

African (AFR) AF: 0.000120 AC: 5 AN: 41576

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

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

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

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: 0.0000882 AC: 6 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.0000514 AC: 6

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 (1)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.9	L
PhyloP100		2.8
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.26
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.050	T
Polyphen		0.95	P
Vest4		0.25
MutPred		0.32		Loss of solvent accessibility (P = 6e-04)
MVP		0.81
ClinPred		0.85	D
GERP RS		4.0
Varity_R		0.12
gMVP		0.57
Mutation Taster		=89/11	polymorphism

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: rs756154211; hg19: chr16-1259311; COSMIC: COSV108192864; COSMIC: COSV108192864;