16-1213816-C-T

Position:

• chr16-1213816-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021098.3(CACNA1H):​c.4814C>T​(p.Pro1605Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,430,330 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.03

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4814C>T	p.Pro1605Leu	missense_variant	27/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4814C>T	p.Pro1605Leu	missense_variant	27/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.4796C>T	p.Pro1599Leu	missense_variant	25/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.4775C>T	p.Pro1592Leu	missense_variant	27/35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.1052C>T	p.Pro351Leu	missense_variant	9/17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.1037C>T	p.Pro346Leu	missense_variant	10/18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.1019C>T	p.Pro340Leu	missense_variant	9/17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.4752C>T		non_coding_transcript_exon_variant	27/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2665C>T		non_coding_transcript_exon_variant	27/35	5		ENSP00000491488.1
CACNA1H	ENST00000640028.1	n.*2665C>T		3_prime_UTR_variant	27/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1430330 Hom.: 0 Cov.: 31 AF XY: 0.00000282 AC XY: 2 AN XY: 708828

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: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000254 Hom.: 0

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

Mar 10, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1605 of the CACNA1H protein (p.Pro1605Leu). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. 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 expected to disrupt CACNA1H protein function. ClinVar contains an entry for this variant (Variation ID: 573465). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D;D;.
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Uncertain	0.68	D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.2	D;.;D;D
REVEL	Uncertain	0.45
Sift	Benign	0.41	T;.;T;T
Sift4G	Uncertain	0.038	D;.;D;D
Polyphen		0.081	B;.;B;B
Vest4		0.56
MutPred		0.47		Loss of disorder (P = 0.0393);.;.;.;
MVP		0.92
ClinPred		0.93	D
GERP RS		2.8
Varity_R		0.10
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs761945003; hg19: chr16-1263816;