NM_021098.3:c.6179G>A

Variant names:

• chr16-1220111-G-A
• rs1054644
• NM_021098.3:c.6179G>A

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.6179G>A​(p.Arg2060His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,483,932 control chromosomes in the GnomAD database, including 13,314 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. R2060C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.094 (920 hom., cov: 35)
  • Exomes 𝑓: 0.13 (12394 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.429
• Publications: 22 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=0.0051501095).
• BP6: Variant 16-1220111-G-A is Benign according to our data. Variant chr16-1220111-G-A is described in ClinVar as Benign. ClinVar VariationId is 96015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.239 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.6179G>A	p.Arg2060His	missense	Exon 35 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.6161G>A	p.Arg2054His	missense	Exon 34 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.6179G>A	p.Arg2060His	missense	Exon 35 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.6194G>A	p.Arg2065His	missense	Exon 34 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.6164G>A	p.Arg2055His	missense	Exon 34 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.0942 AC: 14328 AN: 152106 Hom.: 922 Cov.: 35

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.0737

Gnomad ASJ AF: 0.0848

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.0985

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.0952

GnomAD2 exomes AF: 0.108 AC: 14677 AN: 135794 AF XY: 0.116

Gnomad AFR exome AF: 0.0227

Gnomad AMR exome AF: 0.0448

Gnomad ASJ exome AF: 0.0775

Gnomad EAS exome AF: 0.0216

Gnomad FIN exome AF: 0.0990

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.130 AC: 173665 AN: 1331708 Hom.: 12394 Cov.: 31 AF XY: 0.133 AC XY: 86695 AN XY: 651552

African (AFR) AF: 0.0218 AC: 591 AN: 27058

American (AMR) AF: 0.0507 AC: 1442 AN: 28440

Ashkenazi Jewish (ASJ) AF: 0.0887 AC: 1770 AN: 19946

East Asian (EAS) AF: 0.0165 AC: 549 AN: 33266

South Asian (SAS) AF: 0.235 AC: 15068 AN: 64170

European-Finnish (FIN) AF: 0.107 AC: 5105 AN: 47864

Middle Eastern (MID) AF: 0.0922 AC: 488 AN: 5292

European-Non Finnish (NFE) AF: 0.135 AC: 142036 AN: 1050904

Other (OTH) AF: 0.121 AC: 6616 AN: 54768

GnomAD4 genome AF: 0.0941 AC: 14323 AN: 152224 Hom.: 920 Cov.: 35 AF XY: 0.0944 AC XY: 7022 AN XY: 74404

African (AFR) AF: 0.0263 AC: 1094 AN: 41552

American (AMR) AF: 0.0737 AC: 1127 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 294 AN: 3468

East Asian (EAS) AF: 0.0234 AC: 121 AN: 5176

South Asian (SAS) AF: 0.250 AC: 1207 AN: 4820

European-Finnish (FIN) AF: 0.0985 AC: 1045 AN: 10612

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9120 AN: 67978

Other (OTH) AF: 0.0947 AC: 200 AN: 2112

Alfa AF: 0.110 Hom.: 786

TwinsUK AF: 0.133 AC: 493

ALSPAC AF: 0.132 AC: 510

ESP6500AA AF: 0.0218 AC: 86

ESP6500EA AF: 0.124 AC: 1025

ExAC AF: 0.106 AC: 12587

Asia WGS AF: 0.130 AC: 452 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jul 05, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	7.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.43
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.33
Sift	Benign	0.25	T
Sift4G	Benign	0.081	T
Polyphen		0.0020	B
Vest4		0.043
ClinPred		0.0014	T
GERP RS		0.24
Varity_R		0.043
gMVP		0.21
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: rs1054644; hg19: chr16-1270111; COSMIC: COSV52352958; COSMIC: COSV52352958;