rs59529743

Variant names:

• chr16-1208189-G-A
• rs59529743
• NM_021098.3:c.3331G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1208189-G-A
• chr16-1208189-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_021098.3(CACNA1H):​c.3331G>A​(p.Gly1111Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,550,434 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G1111G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0052 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (7 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.331
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005903363).
• BP6: Variant 16-1208189-G-A is Benign according to our data. Variant chr16-1208189-G-A is described in ClinVar as Benign. ClinVar VariationId is 460084.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00522 (794/152146) while in subpopulation AFR AF = 0.0174 (721/41522). AF 95% confidence interval is 0.0163. There are 9 homozygotes in GnomAd4. There are 343 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 794 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.3331G>A	p.Gly1111Arg	missense	Exon 16 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.3331G>A	p.Gly1111Arg	missense	Exon 16 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.3331G>A	p.Gly1111Arg	missense	Exon 16 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.3331G>A	p.Gly1111Arg	missense	Exon 16 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.3331G>A	p.Gly1111Arg	missense	Exon 16 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.00518 AC: 788 AN: 152028 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00576

GnomAD2 exomes AF: 0.00132 AC: 199 AN: 151142 AF XY: 0.00105

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000893

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000119

Gnomad OTH exome AF: 0.00160

GnomAD4 exome AF: 0.000644 AC: 901 AN: 1398288 Hom.: 7 Cov.: 33 AF XY: 0.000562 AC XY: 388 AN XY: 690700

African (AFR) AF: 0.0193 AC: 611 AN: 31642

American (AMR) AF: 0.00221 AC: 80 AN: 36280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25210

East Asian (EAS) AF: 0.0000278 AC: 1 AN: 35952

South Asian (SAS) AF: 0.0000502 AC: 4 AN: 79624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45438

Middle Eastern (MID) AF: 0.00231 AC: 10 AN: 4320

European-Non Finnish (NFE) AF: 0.0000906 AC: 98 AN: 1081814

Other (OTH) AF: 0.00167 AC: 97 AN: 58008

GnomAD4 genome AF: 0.00522 AC: 794 AN: 152146 Hom.: 9 Cov.: 33 AF XY: 0.00461 AC XY: 343 AN XY: 74380

African (AFR) AF: 0.0174 AC: 721 AN: 41522

American (AMR) AF: 0.00308 AC: 47 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67984

Other (OTH) AF: 0.00570 AC: 12 AN: 2106

Alfa AF: 0.000637 Hom.: 0

Bravo AF: 0.00639

ESP6500AA AF: 0.00780 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000602 AC: 63

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	8.9
DANN	Benign	0.64
DEOGEN2	Benign	0.091	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0059	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.33
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.19
Sift	Benign	0.35	T
Sift4G	Benign	0.51	T
Polyphen		0.58	P
Vest4		0.21
MutPred		0.28		Gain of solvent accessibility (P = 0.019)
MVP		0.61
ClinPred		0.0061	T
GERP RS		-1.8
Varity_R		0.063
gMVP		0.44
Mutation Taster		=100/0	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: rs59529743; hg19: chr16-1258189; COSMIC: COSV105826242;