16-1153777-C-T

Position:

• chr16-1153777-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021098.3(CACNA1H):​c.40C>T​(p.Pro14Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,074,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.66

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27163875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.40C>T	p.Pro14Ser	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.40C>T	p.Pro14Ser	missense_variant	2/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.40C>T	p.Pro14Ser	missense_variant	1/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.40C>T	p.Pro14Ser	missense_variant	2/35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.40C>T		non_coding_transcript_exon_variant	2/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.40C>T		non_coding_transcript_exon_variant	2/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000372 AC: 4 AN: 1074794 Hom.: 0 Cov.: 32 AF XY: 0.00000196 AC XY: 1 AN XY: 509806

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: 0.00000437

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

Jul 14, 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. ClinVar contains an entry for this variant (Variation ID: 1435382). 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 proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 14 of the CACNA1H protein (p.Pro14Ser). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 05, 2024

Available data are insufficient to determine the clinical significance of the variant at this time. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) Polyphen and MutationTaster predict this amino acid change may be benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.65	T;T;T;.
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.4	L;.;L;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.0	N;.;N;N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		0.26	B;.;B;B
Vest4		0.11
MutPred		0.23		Gain of glycosylation at P14 (P = 0.0082);Gain of glycosylation at P14 (P = 0.0082);Gain of glycosylation at P14 (P = 0.0082);Gain of glycosylation at P14 (P = 0.0082);
MVP		0.61
ClinPred		0.91	D
GERP RS		2.9
Varity_R		0.23
gMVP		0.44

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: rs1270361787; hg19: chr16-1203777;