NM_021098.3:c.5162G>A

Variant names:

• chr16-1215364-G-A
• rs747789914
• NM_021098.3:c.5162G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_021098.3(CACNA1H):​c.5162G>A​(p.Arg1721His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,609,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 9.71

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5162G>A	p.Arg1721His	missense_variant	Exon 29 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5162G>A	p.Arg1721His	missense_variant	Exon 29 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.5144G>A	p.Arg1715His	missense_variant	Exon 27 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.5123G>A	p.Arg1708His	missense_variant	Exon 29 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.1400G>A	p.Arg467His	missense_variant	Exon 11 of 17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.1385G>A	p.Arg462His	missense_variant	Exon 12 of 18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.1367G>A	p.Arg456His	missense_variant	Exon 11 of 17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*243G>A		non_coding_transcript_exon_variant	Exon 29 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3013G>A		non_coding_transcript_exon_variant	Exon 29 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*243G>A		3_prime_UTR_variant	Exon 29 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3013G>A		3_prime_UTR_variant	Exon 29 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151646 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000369 AC: 9 AN: 243956 Hom.: 0 AF XY: 0.0000376 AC XY: 5 AN XY: 132862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000143

Gnomad NFE exome AF: 0.0000454

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1457994 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 725148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000193

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151646 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74110

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000192

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000510 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1

Nov 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Mar 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5162G>A (p.R1721H) alteration is located in exon 29 (coding exon 28) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 5162, causing the arginine (R) at amino acid position 1721 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Aug 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs747789914, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. ClinVar contains an entry for this variant (Variation ID: 585648). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1721 of the CACNA1H protein (p.Arg1721His). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Mar 12, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;.
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.7	H;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.0	D;.;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.84
MVP		0.98
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.95
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs747789914; hg19: chr16-1265364;