rs57633676

Positions:

• chr16-1208064-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.3206G>A​(p.Arg1069Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,605,378 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (4 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.16

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]

CACNA1H (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056758523).
• BP6: Variant 16-1208064-G-A is Benign according to our data. Variant chr16-1208064-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1208064-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00544 (828/152204) while in subpopulation AFR AF= 0.019 (789/41522). AF 95% confidence interval is 0.0179. There are 7 homozygotes in gnomad4. There are 404 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 828 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.3206G>A	p.Arg1069Gln	missense_variant	16/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.3206G>A	p.Arg1069Gln	missense_variant	16/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.3206G>A	p.Arg1069Gln	missense_variant	15/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.3167G>A	p.Arg1056Gln	missense_variant	16/35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.3206G>A		non_coding_transcript_exon_variant	16/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*1119G>A		non_coding_transcript_exon_variant	16/35	5		ENSP00000491488.1
CACNA1H	ENST00000640028.1	n.*1119G>A		3_prime_UTR_variant	16/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 826 AN: 152086 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

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: 0.0000882

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00125 AC: 291 AN: 232472 Hom.: 1 AF XY: 0.00100 AC XY: 127 AN XY: 126742

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.000933

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000410

Gnomad SAS exome AF: 0.0000352

Gnomad FIN exome AF: 0.000147

Gnomad NFE exome AF: 0.0000480

Gnomad OTH exome AF: 0.000524

GnomAD4 exome AF: 0.000547 AC: 795 AN: 1453174 Hom.: 4 Cov.: 33 AF XY: 0.000475 AC XY: 343 AN XY: 722066

Gnomad4 AFR exome AF: 0.0181

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000229

Gnomad4 SAS exome AF: 0.0000946

Gnomad4 FIN exome AF: 0.000272

Gnomad4 NFE exome AF: 0.0000370

Gnomad4 OTH exome AF: 0.00117

GnomAD4 genome AF: 0.00544 AC: 828 AN: 152204 Hom.: 7 Cov.: 32 AF XY: 0.00543 AC XY: 404 AN XY: 74404

Gnomad4 AFR AF: 0.0190

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00132 Hom.: 2

Bravo AF: 0.00606

ESP6500AA AF: 0.0173 AC: 71

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00175 AC: 211

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 14, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T;.;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.0056
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.80	T;T;T;.
MetaRNN	Benign	0.0057	T;T;T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.4	M;.;M;M
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.2	N;.;N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.025	D;.;D;D
Sift4G	Benign	0.16	T;.;T;T
Polyphen		1.0	D;.;D;D
Vest4		0.18
MVP		0.89
ClinPred		0.016	T
GERP RS		3.0
Varity_R		0.20
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs57633676; hg19: chr16-1258064;