16-1153778-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BP6

The NM_021098.3(CACNA1H):c.41C>T(p.Pro14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000619 in 1,226,856 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P14S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.66

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35292497).
• BP6: Variant 16-1153778-C-T is Benign according to our data. Variant chr16-1153778-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1475245.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.41C>T	p.Pro14Leu	missense_variant	2/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.41C>T	p.Pro14Leu	missense_variant	2/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000265 AC: 4 AN: 150980 Hom.: 0 Cov.: 30

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: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000669 AC: 72 AN: 1075876 Hom.: 0 Cov.: 32 AF XY: 0.0000725 AC XY: 37 AN XY: 510422

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: 0.000162

Gnomad4 FIN exome AF: 0.0000460

Gnomad4 NFE exome AF: 0.0000687

Gnomad4 OTH exome AF: 0.0000940

GnomAD4 genome AF: 0.0000265 AC: 4 AN: 150980 Hom.: 0 Cov.: 30 AF XY: 0.0000407 AC XY: 3 AN XY: 73714

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000302

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

May 26, 2022

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.71	T;T;T;.
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.4	L;.;L;L
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.7	N;.;N;N
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		0.98	D;.;D;D
Vest4		0.20
MutPred		0.30		Gain of helix (P = 0.005);Gain of helix (P = 0.005);Gain of helix (P = 0.005);Gain of helix (P = 0.005);
MVP		0.74
ClinPred		0.94	D
GERP RS		2.9
Varity_R		0.22
gMVP		0.42

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: rs1263557227; hg19: chr16-1203778;