rs60526088

Positions:

• chr16-1218542-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021098.3(CACNA1H):​c.5778G>A​(p.Ser1926Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,558,338 control chromosomes in the GnomAD database, including 1,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (321 hom., cov: 31)
  • Exomes 𝑓: 0.025 (711 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.27

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-1218542-G-A is Benign according to our data. Variant chr16-1218542-G-A is described in ClinVar as [Benign]. Clinvar id is 446955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5778G>A	p.Ser1926Ser	synonymous_variant	33/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5778G>A	p.Ser1926Ser	synonymous_variant	33/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.5760G>A	p.Ser1920Ser	synonymous_variant	31/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.5739G>A	p.Ser1913Ser	synonymous_variant	33/35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.2016G>A	p.Ser672Ser	synonymous_variant	15/17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.2001G>A	p.Ser667Ser	synonymous_variant	16/18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.1983G>A	p.Ser661Ser	synonymous_variant	15/17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*859G>A		non_coding_transcript_exon_variant	33/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3629G>A		non_coding_transcript_exon_variant	33/35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*859G>A		3_prime_UTR_variant	33/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3629G>A		3_prime_UTR_variant	33/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.0462 AC: 7036 AN: 152130 Hom.: 313 Cov.: 31

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0319

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.0974

Gnomad SAS AF: 0.0418

Gnomad FIN AF: 0.00782

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0355 AC: 5889 AN: 165988 Hom.: 181 AF XY: 0.0342 AC XY: 3033 AN XY: 88586

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.0456

Gnomad ASJ exome AF: 0.00704

Gnomad EAS exome AF: 0.0916

Gnomad SAS exome AF: 0.0408

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.0200

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0248 AC: 34846 AN: 1406090 Hom.: 711 Cov.: 38 AF XY: 0.0247 AC XY: 17185 AN XY: 694384

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.0440

Gnomad4 ASJ exome AF: 0.00657

Gnomad4 EAS exome AF: 0.0815

Gnomad4 SAS exome AF: 0.0378

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.0194

Gnomad4 OTH exome AF: 0.0319

GnomAD4 genome AF: 0.0464 AC: 7067 AN: 152248 Hom.: 321 Cov.: 31 AF XY: 0.0458 AC XY: 3409 AN XY: 74444

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0319

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.0978

Gnomad4 SAS AF: 0.0418

Gnomad4 FIN AF: 0.00782

Gnomad4 NFE AF: 0.0180

Gnomad4 OTH AF: 0.0383

Alfa AF: 0.0266 Hom.: 44

Bravo AF: 0.0502

Asia WGS AF: 0.0750 AC: 260 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 27, 2017

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.18
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs60526088; hg19: chr16-1268542;