rs374272094

Positions:

• chr16-1205204-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PP3_Moderate BP6 BS1 BS2

The NM_021098.3(CACNA1H):​c.2542G>A​(p.Gly848Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,030 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 9.69

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 -7 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• BP6: Variant 16-1205204-G-A is Benign according to our data. Variant chr16-1205204-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 568423.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000184 (28/152314) while in subpopulation AFR AF= 0.000553 (23/41570). AF 95% confidence interval is 0.000378. There are 1 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.2542G>A	p.Gly848Ser	missense_variant	11/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.2542G>A	p.Gly848Ser	missense_variant	11/35	1	NM_021098.3	ENSP00000334198	P4

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152196 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000764 AC: 19 AN: 248576 Hom.: 0 AF XY: 0.0000666 AC XY: 9 AN XY: 135084

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000622

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1460716 Hom.: 0 Cov.: 32 AF XY: 0.0000399 AC XY: 29 AN XY: 726634

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152314 Hom.: 1 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74472

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000152 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.000478 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000578 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 21, 2019

Variant summary: CACNA1H c.2542G>A (p.Gly848Ser) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 249036 control chromosomes (gnomAD). c.2542G>A has been reported in the literature in a child with epilepsy and Autism Spectrum Disorder (Long_2019). It has also been reported in an individual affected with childhood absence epilepsy who had inherited the variant from their unaffected parent (Chen_2003). This study and another study (PMID: 17696120) following testing of multiple individuals affected with idiopathic generalized epilepsy, including childhood absence epilepsy, concluded that CACNA1H variants represented susceptibility alleles involved in the pathogenesis of a multifactorial disorder. However, no definitive conclusions could be drawn from these studies since no other genes indicated to be associated with the disorder were examined and since there was lack of segregation with disease in the majority of the families assessed. These data do not allow any conclusion about variant significance. Two functional studies were contradictory on their findings and did not allow convincing conclusions about the variant effect. Specifically, one study noted changes in activation and inactivation but not deactivation kinetics for the variant (Peloquin_2006) while the other study showed opposite results finding no alterations in activation and inactivation kinetics but small changes in the deactivation kinetics at very negative voltages (Vitko_2005). A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;.
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.8	D;.;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.020	D;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.88
MVP		0.98
ClinPred		0.79	D
GERP RS		3.0
Varity_R		0.63
gMVP		0.91

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: rs374272094; hg19: chr16-1255204; COSMIC: COSV62003956; COSMIC: COSV62003956;