rs58124832

Variant names:

• chr16-1218376-G-A
• rs58124832
• NM_021098.3:c.5612G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1218376-G-A
• chr16-1218376-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021098.3(CACNA1H):​c.5612G>A​(p.Arg1871Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0573 in 1,561,046 control chromosomes in the GnomAD database, including 3,036 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R1871L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.045 (230 hom., cov: 34)
  • Exomes 𝑓: 0.059 (2806 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.23
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018953979).
• BP6: Variant 16-1218376-G-A is Benign according to our data. Variant chr16-1218376-G-A is described in ClinVar as Benign. ClinVar VariationId is 585651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.072 is higher than 0.05.

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.5612G>A	p.Arg1871Gln	missense	Exon 33 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.5594G>A	p.Arg1865Gln	missense	Exon 32 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.5612G>A	p.Arg1871Gln	missense	Exon 33 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.5627G>A	p.Arg1876Gln	missense	Exon 32 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.5630G>A	p.Arg1877Gln	missense	Exon 32 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.0451 AC: 6863 AN: 152190 Hom.: 229 Cov.: 34

Gnomad AFR AF: 0.00914

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0400

Gnomad ASJ AF: 0.0838

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0778

Gnomad FIN AF: 0.0488

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0645

Gnomad OTH AF: 0.0559

GnomAD2 exomes AF: 0.0548 AC: 9431 AN: 172182 AF XY: 0.0588

Gnomad AFR exome AF: 0.00844

Gnomad AMR exome AF: 0.0302

Gnomad ASJ exome AF: 0.0870

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.0489

Gnomad NFE exome AF: 0.0648

Gnomad OTH exome AF: 0.0667

GnomAD4 exome AF: 0.0586 AC: 82512 AN: 1408738 Hom.: 2806 Cov.: 33 AF XY: 0.0597 AC XY: 41527 AN XY: 695890

African (AFR) AF: 0.00741 AC: 237 AN: 31992

American (AMR) AF: 0.0312 AC: 1146 AN: 36738

Ashkenazi Jewish (ASJ) AF: 0.0878 AC: 2224 AN: 25338

East Asian (EAS) AF: 0.000192 AC: 7 AN: 36374

South Asian (SAS) AF: 0.0840 AC: 6692 AN: 79712

European-Finnish (FIN) AF: 0.0503 AC: 2450 AN: 48662

Middle Eastern (MID) AF: 0.0781 AC: 446 AN: 5708

European-Non Finnish (NFE) AF: 0.0607 AC: 65913 AN: 1085618

Other (OTH) AF: 0.0580 AC: 3397 AN: 58596

GnomAD4 genome AF: 0.0451 AC: 6865 AN: 152308 Hom.: 230 Cov.: 34 AF XY: 0.0438 AC XY: 3259 AN XY: 74474

African (AFR) AF: 0.00912 AC: 379 AN: 41570

American (AMR) AF: 0.0400 AC: 612 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0838 AC: 291 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5178

South Asian (SAS) AF: 0.0785 AC: 379 AN: 4830

European-Finnish (FIN) AF: 0.0488 AC: 518 AN: 10616

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0645 AC: 4387 AN: 68012

Other (OTH) AF: 0.0549 AC: 116 AN: 2114

Alfa AF: 0.0569 Hom.: 440

Bravo AF: 0.0400

TwinsUK AF: 0.0593 AC: 220

ALSPAC AF: 0.0576 AC: 222

ESP6500AA AF: 0.00853 AC: 36

ESP6500EA AF: 0.0583 AC: 489

ExAC AF: 0.0410 AC: 4646

Asia WGS AF: 0.0300 AC: 105 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.28
Sift	Benign	0.49	T
Sift4G	Benign	0.89	T
Polyphen		0.16	B
Vest4		0.24
ClinPred		0.0021	T
GERP RS		1.0
Varity_R		0.068
gMVP		0.37
Mutation Taster		=100/0	polymorphism (auto)

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: rs58124832; hg19: chr16-1268376; COSMIC: COSV52357919; COSMIC: COSV52357919;