rs554063452

Variant names:

• chr16-1219114-G-A
• rs554063452
• NM_021098.3:c.6032G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1219114-G-A
• chr16-1219114-G-C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_021098.3(CACNA1H):​c.6032G>A​(p.Arg2011Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000674 in 1,542,950 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. R2011W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000099 (1 hom., cov: 34)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.673
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.123465806).
• BP6: Variant 16-1219114-G-A is Benign according to our data. Variant chr16-1219114-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 460158.
• BS2: High AC in GnomAd4 at 15 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.6032G>A	p.Arg2011Gln	missense	Exon 34 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.6014G>A	p.Arg2005Gln	missense	Exon 33 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.6032G>A	p.Arg2011Gln	missense	Exon 34 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.6047G>A	p.Arg2016Gln	missense	Exon 33 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.6017G>A	p.Arg2006Gln	missense	Exon 33 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152134 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000482 AC: 7 AN: 145250 AF XY: 0.0000386

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000825

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000730

Gnomad OTH exome AF: 0.000240

GnomAD4 exome AF: 0.0000640 AC: 89 AN: 1390698 Hom.: 0 Cov.: 34 AF XY: 0.0000584 AC XY: 40 AN XY: 685136

African (AFR) AF: 0.0000635 AC: 2 AN: 31478

American (AMR) AF: 0.000113 AC: 4 AN: 35366

Ashkenazi Jewish (ASJ) AF: 0.0000403 AC: 1 AN: 24844

East Asian (EAS) AF: 0.00 AC: 0 AN: 35574

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5660

European-Non Finnish (NFE) AF: 0.0000688 AC: 74 AN: 1074814

Other (OTH) AF: 0.000121 AC: 7 AN: 57666

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152252 Hom.: 1 Cov.: 34 AF XY: 0.0000940 AC XY: 7 AN XY: 74436

African (AFR) AF: 0.00 AC: 0 AN: 41534

American (AMR) AF: 0.000261 AC: 4 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68008

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.0000985 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000137 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.67
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.25
Sift	Benign	0.031	D
Sift4G	Benign	0.11	T
Polyphen		0.0030	B
Vest4		0.27
MVP		0.78
ClinPred		0.13	T
GERP RS		2.4
Varity_R		0.10
gMVP		0.32
Mutation Taster		=94/6	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: rs554063452; hg19: chr16-1269114; COSMIC: COSV52356174; COSMIC: COSV52356174;