rs201449513

chr16-1202278-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):c.1828A>G(p.Thr610Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000759 in 1,581,092 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (1 hom., cov: 34)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.504

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01181522).
• BP6: Variant 16-1202278-A-G is Benign according to our data. Variant chr16-1202278-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 460053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000144 (22/152320) while in subpopulation EAS AF= 0.00406 (21/5178). AF 95% confidence interval is 0.00272. There are 1 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.1828A>G	p.Thr610Ala	missense_variant	9/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.1828A>G	p.Thr610Ala	missense_variant	9/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152202 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00405

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000126 AC: 24 AN: 190914 Hom.: 0 AF XY: 0.0000955 AC XY: 10 AN XY: 104754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000340

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00142

Gnomad SAS exome AF: 0.0000804

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000198

GnomAD4 exome AF: 0.0000686 AC: 98 AN: 1428772 Hom.: 0 Cov.: 57 AF XY: 0.0000622 AC XY: 44 AN XY: 707882

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000248

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00192

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.000236

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152320 Hom.: 1 Cov.: 34 AF XY: 0.000148 AC XY: 11 AN XY: 74494

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00406

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000159

ExAC AF: 0.0000942 AC: 11

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 06, 2021

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	0.13
Dann	Benign	0.43
DEOGEN2	Benign	0.077	T;.;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.15	T;T;T;.
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.36	N;.;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.13	N;.;N;N
REVEL	Benign	0.28
Sift	Benign	0.50	T;.;T;T
Sift4G	Benign	0.91	T;.;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.018
MVP		0.56
ClinPred		0.019	T
GERP RS		-4.2
Varity_R		0.039
gMVP		0.22

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: rs201449513; hg19: chr16-1252278;