rs201009269

chr16-1201958-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_021098.3(CACNA1H):c.1508G>A(p.Arg503His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,545,504 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R503C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.89

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023483157).
• BP6: Variant 16-1201958-G-A is Benign according to our data. Variant chr16-1201958-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 460048.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000433 (66/152288) while in subpopulation AFR AF= 0.0013 (54/41556). AF 95% confidence interval is 0.00102. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.1508G>A	p.Arg503His	missense_variant	9/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.1508G>A	p.Arg503His	missense_variant	9/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152172 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000844 AC: 12 AN: 142242 Hom.: 0 AF XY: 0.0000261 AC XY: 2 AN XY: 76720

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.0000409

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000192

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000112 AC: 156 AN: 1393216 Hom.: 1 Cov.: 36 AF XY: 0.0000976 AC XY: 67 AN XY: 686594

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.0000216

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.000208

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152288 Hom.: 0 Cov.: 34 AF XY: 0.000349 AC XY: 26 AN XY: 74466

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0107 Hom.: 243

Bravo AF: 0.000480

ESP6500AA AF: 0.000563 AC: 2

ESP6500EA AF: 0.000279 AC: 2

ExAC AF: 0.000108 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

CACNA1H NM_021098.2 exon 9 p.Arg503His (c.1508G>A): This variant has not been reported in the literature but is present in 0.1% (16/15288) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-1251958-G-A). This variant is present in ClinVar (Variation ID:460048). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2021

The c.1508G>A (p.R503H) alteration is located in exon 9 (coding exon 8) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 1508, causing the arginine (R) at amino acid position 503 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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;.;.
Eigen	Benign	0.014
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.85	T;T;T;.
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.023	T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.0	M;.;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.5	N;.;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.095	T;.;T;T
Sift4G	Benign	0.16	T;.;T;T
Polyphen		1.0	D;.;D;D
Vest4		0.23
MVP		0.88
ClinPred		0.021	T
GERP RS		2.6
Varity_R		0.090
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs201009269; hg19: chr16-1251958; COSMIC: COSV100673409; COSMIC: COSV100673409;