16-1153742-C-A

Position:

• chr16-1153742-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_021098.3(CACNA1H):​c.5C>A​(p.Thr2Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000756 in 1,058,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.112

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39324218).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5C>A	p.Thr2Asn	missense_variant	2/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5C>A	p.Thr2Asn	missense_variant	2/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.5C>A	p.Thr2Asn	missense_variant	1/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.5C>A	p.Thr2Asn	missense_variant	2/35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.5C>A		non_coding_transcript_exon_variant	2/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.5C>A		non_coding_transcript_exon_variant	2/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000756 AC: 8 AN: 1058838 Hom.: 0 Cov.: 31 AF XY: 0.00000999 AC XY: 5 AN XY: 500732

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000772

Gnomad4 OTH exome AF: 0.0000241

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1H protein function. This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 2 of the CACNA1H protein (p.Thr2Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.097	T;.;.;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.41	T;T;T;.
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.1	L;.;L;L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.59	N;.;N;N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Benign	0.080	T;.;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.16
MutPred		0.17		Loss of phosphorylation at T2 (P = 0.0325);Loss of phosphorylation at T2 (P = 0.0325);Loss of phosphorylation at T2 (P = 0.0325);Loss of phosphorylation at T2 (P = 0.0325);
MVP		0.50
ClinPred		0.22	T
GERP RS		0.71
Varity_R		0.16
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1335993092; hg19: chr16-1203742;