NM_021098.3:c.5675G>T

Variant names:

• chr16-1218439-G-T
• rs58667649
• NM_021098.3:c.5675G>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.5675G>T​(p.Arg1892Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,552,680 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. R1892H) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (12 hom., cov: 34)
  • Exomes 𝑓: 0.00052 (3 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.683
• Publications: 8 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=0.005491793).
• BP6: Variant 16-1218439-G-T is Benign according to our data. Variant chr16-1218439-G-T is described in ClinVar as Benign. ClinVar VariationId is 460151.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 = 0.00566 (862/152308) while in subpopulation AFR AF = 0.0193 (804/41556). AF 95% confidence interval is 0.0182. There are 12 homozygotes in GnomAd4. There are 403 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 862 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.5675G>T	p.Arg1892Leu	missense	Exon 33 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.5657G>T	p.Arg1886Leu	missense	Exon 32 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.5675G>T	p.Arg1892Leu	missense	Exon 33 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.5690G>T	p.Arg1897Leu	missense	Exon 32 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.5693G>T	p.Arg1898Leu	missense	Exon 32 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.00565 AC: 860 AN: 152190 Hom.: 12 Cov.: 34

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00121 AC: 191 AN: 158130 AF XY: 0.000835

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.000965

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000160

Gnomad OTH exome AF: 0.00112

GnomAD4 exome AF: 0.000518 AC: 725 AN: 1400372 Hom.: 3 Cov.: 33 AF XY: 0.000447 AC XY: 309 AN XY: 690952

African (AFR) AF: 0.0181 AC: 574 AN: 31698

American (AMR) AF: 0.00120 AC: 43 AN: 35938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25190

East Asian (EAS) AF: 0.00 AC: 0 AN: 35852

South Asian (SAS) AF: 0.0000378 AC: 3 AN: 79348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47854

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5666

European-Non Finnish (NFE) AF: 0.0000130 AC: 14 AN: 1080634

Other (OTH) AF: 0.00146 AC: 85 AN: 58192

GnomAD4 genome AF: 0.00566 AC: 862 AN: 152308 Hom.: 12 Cov.: 34 AF XY: 0.00541 AC XY: 403 AN XY: 74466

African (AFR) AF: 0.0193 AC: 804 AN: 41556

American (AMR) AF: 0.00307 AC: 47 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00651

ESP6500AA AF: 0.0124 AC: 51

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000875 AC: 94

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 25, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

Jan 08, 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	0.084
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	2.1
DANN	Benign	0.76
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0055	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.68
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.30
Sift	Benign	0.33	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.66
ClinPred		0.0026	T
GERP RS		-0.61
Varity_R		0.10
gMVP		0.39
Mutation Taster		=100/0	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: rs58667649; hg19: chr16-1268439;