16-1153750-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_021098.3(CACNA1H):c.13G>A(p.Ala5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,212,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. A5S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.369

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.099538594).
• BP6: Variant 16-1153750-G-A is Benign according to our data. Variant chr16-1153750-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 800247.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000536 (81/151074) while in subpopulation AFR AF= 0.00184 (76/41342). AF 95% confidence interval is 0.00151. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 81 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.13G>A	p.Ala5Thr	missense_variant	2/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.13G>A	p.Ala5Thr	missense_variant	2/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.000537 AC: 81 AN: 150972 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.000965

GnomAD4 exome AF: 0.0000500 AC: 53 AN: 1060948 Hom.: 0 Cov.: 31 AF XY: 0.0000319 AC XY: 16 AN XY: 501894

Gnomad4 AFR exome AF: 0.00230

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: 0.00000110

Gnomad4 OTH exome AF: 0.0000480

GnomAD4 genome AF: 0.000536 AC: 81 AN: 151074 Hom.: 0 Cov.: 30 AF XY: 0.000569 AC XY: 42 AN XY: 73840

Gnomad4 AFR AF: 0.00184

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.000955

Bravo AF: 0.000438

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.13G>A (p.A5T) alteration is located in exon 2 (coding exon 1) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 13, causing the alanine (A) at amino acid position 5 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	9.3
Dann	Benign	0.85
DEOGEN2	Benign	0.097	T;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.46	T;T;T;.
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.0	N;.;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.10	N;.;N;N
REVEL	Benign	0.29
Sift	Benign	0.73	T;.;T;T
Sift4G	Benign	0.62	T;.;T;T
Polyphen		0.0040	B;.;B;B
Vest4		0.033
MutPred		0.12		Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);
MVP		0.34
ClinPred		0.017	T
GERP RS		0.79
Varity_R		0.038
gMVP		0.27

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: rs948561024; hg19: chr16-1203750;