rs746748953

chr16-1201855-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_Strong BP6

The NM_021098.3(CACNA1H):c.1405C>T(p.Arg469Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,563,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R469H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.47

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 3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• BP6: Variant 16-1201855-C-T is Benign according to our data. Variant chr16-1201855-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 529572.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.1405C>T	p.Arg469Cys	missense_variant	9/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.1405C>T	p.Arg469Cys	missense_variant	9/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152258 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000117 AC: 2 AN: 171118 Hom.: 0 AF XY: 0.0000109 AC XY: 1 AN XY: 91622

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000143

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000120 AC: 17 AN: 1411738 Hom.: 0 Cov.: 36 AF XY: 0.00000860 AC XY: 6 AN XY: 697604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000270

Gnomad4 ASJ exome AF: 0.0000395

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.0000205

Gnomad4 NFE exome AF: 0.0000110

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152258 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74392

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000867 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 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

Fulgent Genetics, Fulgent Genetics

Aug 09, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D;D;D;.
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;.;M;M
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.9	D;.;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.013	D;.;D;D
Sift4G	Benign	0.062	T;.;T;T
Polyphen		1.0	D;.;D;D
Vest4		0.73
MutPred		0.79		Loss of helix (P = 0.0237);.;Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);
MVP		0.98
ClinPred		0.91	D
GERP RS		3.9
Varity_R		0.59
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs746748953; hg19: chr16-1251855; COSMIC: COSV61996628; COSMIC: COSV61996628;