NM_021098.3:c.3589G>A

Variant names:

• chr16-1209257-G-A
• rs751423106
• NM_021098.3:c.3589G>A

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.3589G>A​(p.Glu1197Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000909 in 1,546,578 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (1 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 3.48
• Publications: 1 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07822651).
• BP6: Variant 16-1209257-G-A is Benign according to our data. Variant chr16-1209257-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529611.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000453 (69/152238) while in subpopulation NFE AF = 0.000794 (54/67990). AF 95% confidence interval is 0.000625. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 69 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.3589G>A	p.Glu1197Lys	missense	Exon 17 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.3589G>A	p.Glu1197Lys	missense	Exon 17 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.3589G>A	p.Glu1197Lys	missense	Exon 17 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.3589G>A	p.Glu1197Lys	missense	Exon 17 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.3589G>A	p.Glu1197Lys	missense	Exon 17 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000443 AC: 63 AN: 142194 AF XY: 0.000458

Gnomad AFR exome AF: 0.000159

Gnomad AMR exome AF: 0.0000801

Gnomad ASJ exome AF: 0.000985

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000104

Gnomad NFE exome AF: 0.000835

Gnomad OTH exome AF: 0.000941

GnomAD4 exome AF: 0.000959 AC: 1337 AN: 1394340 Hom.: 1 Cov.: 31 AF XY: 0.000996 AC XY: 686 AN XY: 688942

African (AFR) AF: 0.000191 AC: 6 AN: 31370

American (AMR) AF: 0.0000829 AC: 3 AN: 36184

Ashkenazi Jewish (ASJ) AF: 0.000638 AC: 16 AN: 25086

East Asian (EAS) AF: 0.00 AC: 0 AN: 35758

South Asian (SAS) AF: 0.0000375 AC: 3 AN: 79918

European-Finnish (FIN) AF: 0.0000489 AC: 2 AN: 40916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00118 AC: 1273 AN: 1081466

Other (OTH) AF: 0.000587 AC: 34 AN: 57966

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000390 AC XY: 29 AN XY: 74412

African (AFR) AF: 0.000192 AC: 8 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 67990

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

Alfa AF: 0.000809 Hom.: 0

Bravo AF: 0.000487

ExAC AF: 0.000242 AC: 26

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	CACNA1H-related disorder (1)
-	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	0.24
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.078	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		3.5
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.35
Sift	Benign	0.26	T
Sift4G	Benign	0.78	T
Polyphen		0.99	D
Vest4		0.49
MVP		0.87
ClinPred		0.066	T
GERP RS		4.2
Varity_R		0.21
gMVP		0.55
Mutation Taster		=86/14	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: rs751423106; hg19: chr16-1259257; COSMIC: COSV62001337; COSMIC: COSV62001337;