rs58394372

Variant names:

• chr16-1209290-G-A
• rs58394372
• NM_021098.3:c.3622G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1209290-G-A
• chr16-1209290-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.3622G>A​(p.Ala1208Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000633 in 1,577,374 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1208A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.42
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006581396).
• BP6: Variant 16-1209290-G-A is Benign according to our data. Variant chr16-1209290-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00177 (269/152252) while in subpopulation AFR AF = 0.00563 (234/41570). AF 95% confidence interval is 0.00504. There are 2 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 269 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.3622G>A	p.Ala1208Thr	missense	Exon 17 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.3622G>A	p.Ala1208Thr	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.3622G>A	p.Ala1208Thr	missense	Exon 17 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.3622G>A	p.Ala1208Thr	missense	Exon 17 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.3622G>A	p.Ala1208Thr	missense	Exon 17 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 267 AN: 152138 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000479 AC: 92 AN: 191946 AF XY: 0.000411

Gnomad AFR exome AF: 0.00446

Gnomad AMR exome AF: 0.000395

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000681

Gnomad FIN exome AF: 0.0000989

Gnomad NFE exome AF: 0.000340

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000512 AC: 729 AN: 1425122 Hom.: 1 Cov.: 31 AF XY: 0.000493 AC XY: 349 AN XY: 707726

African (AFR) AF: 0.00572 AC: 188 AN: 32862

American (AMR) AF: 0.000316 AC: 13 AN: 41126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25684

East Asian (EAS) AF: 0.0000527 AC: 2 AN: 37932

South Asian (SAS) AF: 0.0000481 AC: 4 AN: 83234

European-Finnish (FIN) AF: 0.0000518 AC: 2 AN: 38596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.000445 AC: 490 AN: 1100702

Other (OTH) AF: 0.000506 AC: 30 AN: 59258

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152252 Hom.: 2 Cov.: 33 AF XY: 0.00173 AC XY: 129 AN XY: 74434

African (AFR) AF: 0.00563 AC: 234 AN: 41570

American (AMR) AF: 0.000719 AC: 11 AN: 15300

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

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 67992

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000622 Hom.: 0

Bravo AF: 0.00194

ESP6500AA AF: 0.00312 AC: 11

ESP6500EA AF: 0.000533 AC: 4

ExAC AF: 0.000513 AC: 59

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.019
DANN	Benign	0.80
DEOGEN2	Benign	0.13	T
Eigen	Benign	-2.5
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0066	T
MetaSVM	Uncertain	-0.037	T
MutationAssessor	Benign	-0.47	N
PhyloP100		-3.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.22
Sift	Benign	0.70	T
Sift4G	Benign	0.39	T
Polyphen		0.0020	B
Vest4		0.047
MVP		0.48
ClinPred		0.0032	T
GERP RS		-8.4
Varity_R		0.029
gMVP		0.37
Mutation Taster		=99/1	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: rs58394372; hg19: chr16-1259290; COSMIC: COSV100673545; COSMIC: COSV100673545;