rs370039255

Positions:

• chr16-1209223-G-A
• chr16-1209223-G-C
• chr16-1209223-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_021098.3(CACNA1H):​c.3555G>A​(p.Ala1185=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,545,024 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1185A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -3.15

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-1209223-G-A is Benign according to our data. Variant chr16-1209223-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96010.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000676 (103/152280) while in subpopulation AMR AF= 0.00118 (18/15306). AF 95% confidence interval is 0.000928. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.3555G>A	p.Ala1185=	synonymous_variant	17/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.3555G>A	p.Ala1185=	synonymous_variant	17/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.00113

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000739 AC: 102 AN: 137960 Hom.: 0 AF XY: 0.000596 AC XY: 45 AN XY: 75526

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00164

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000195

Gnomad SAS exome AF: 0.000182

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000977

Gnomad OTH exome AF: 0.00146

GnomAD4 exome AF: 0.00119 AC: 1659 AN: 1392744 Hom.: 1 Cov.: 31 AF XY: 0.00117 AC XY: 801 AN XY: 687386

Gnomad4 AFR exome AF: 0.000227

Gnomad4 AMR exome AF: 0.00151

Gnomad4 ASJ exome AF: 0.0000400

Gnomad4 EAS exome AF: 0.0000565

Gnomad4 SAS exome AF: 0.000165

Gnomad4 FIN exome AF: 0.0000446

Gnomad4 NFE exome AF: 0.00139

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.000484 AC XY: 36 AN XY: 74456

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000745 Hom.: 0

Bravo AF: 0.000914

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	CACNA1H: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2013	- -

CACNA1H-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 12, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.13
DANN	Benign	0.76

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: rs370039255; hg19: chr16-1259223;