rs61056448

chr16-1202152-G-A

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.1702G>A(p.Asp568Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,550,318 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D568V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (19 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.30

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=0.00608176).
• BP6: Variant 16-1202152-G-A is Benign according to our data. Variant chr16-1202152-G-A is described in ClinVar as [Benign]. Clinvar id is 460050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202152-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00101 (154/152366) while in subpopulation SAS AF= 0.00455 (22/4832). AF 95% confidence interval is 0.00308. There are 1 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 152 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.1702G>A	p.Asp568Asn	missense_variant	9/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.1702G>A	p.Asp568Asn	missense_variant	9/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.000998 AC: 152 AN: 152248 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00194 AC: 283 AN: 146046 Hom.: 3 AF XY: 0.00227 AC XY: 179 AN XY: 78996

Gnomad AFR exome AF: 0.000149

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.0000929

Gnomad SAS exome AF: 0.00279

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00211

GnomAD4 exome AF: 0.00113 AC: 1574 AN: 1397952 Hom.: 19 Cov.: 36 AF XY: 0.00126 AC XY: 867 AN XY: 689642

Gnomad4 AFR exome AF: 0.000475

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.0145

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00298

Gnomad4 FIN exome AF: 0.0000212

Gnomad4 NFE exome AF: 0.000646

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152366 Hom.: 1 Cov.: 34 AF XY: 0.00105 AC XY: 78 AN XY: 74506

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00213 Hom.: 1

Bravo AF: 0.00114

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000593 AC: 4

ExAC AF: 0.00103 AC: 102

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 08, 2018

- -

Epilepsy, childhood absence, susceptibility to, 6 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	16
Dann	Benign	0.85
DEOGEN2	Benign	0.12	T;.;.;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	D;D;D;.
MetaRNN	Benign	0.0061	T;T;T;T
MetaSVM	Uncertain	-0.094	T
MutationAssessor	Benign	1.0	L;.;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.30	N;.;N;N
REVEL	Benign	0.15
Sift	Benign	0.44	T;.;T;T
Sift4G	Benign	0.49	T;.;T;T
Polyphen		0.0040	B;.;B;B
Vest4		0.27
MVP		0.63
ClinPred		0.0021	T
GERP RS		2.9
Varity_R		0.063
gMVP		0.39

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: rs61056448; hg19: chr16-1252152; COSMIC: COSV62005400; COSMIC: COSV62005400;