rs28365124

Positions:

• chr16-1210636-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.4023G>A​(p.Ala1341Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0593 in 1,605,038 control chromosomes in the GnomAD database, including 3,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (249 hom., cov: 33)
  • Exomes 𝑓: 0.061 (3083 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.34

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=-0.85).
• BP6: Variant 16-1210636-G-A is Benign according to our data. Variant chr16-1210636-G-A is described in ClinVar as [Benign]. Clinvar id is 585639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210636-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4023G>A	p.Ala1341Ala	synonymous_variant	20/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4023G>A	p.Ala1341Ala	synonymous_variant	20/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.4023G>A	p.Ala1341Ala	synonymous_variant	19/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.3984G>A	p.Ala1328Ala	synonymous_variant	20/35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.246G>A	p.Ala82Ala	synonymous_variant	3/17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.246G>A	p.Ala82Ala	synonymous_variant	3/18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.246G>A	p.Ala82Ala	synonymous_variant	3/17	1		ENSP00000454581.2
CACNA1H	ENST00000637236.2	n.386G>A		non_coding_transcript_exon_variant	4/6	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.4023G>A		non_coding_transcript_exon_variant	20/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*1936G>A		non_coding_transcript_exon_variant	20/35	5		ENSP00000491488.1
CACNA1H	ENST00000640028.1	n.*1936G>A		3_prime_UTR_variant	20/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 7160 AN: 152140 Hom.: 248 Cov.: 33

Gnomad AFR AF: 0.00948

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0435

Gnomad ASJ AF: 0.0916

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0828

Gnomad FIN AF: 0.0498

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0669

Gnomad OTH AF: 0.0569

GnomAD3 exomes AF: 0.0553 AC: 13321 AN: 241058 Hom.: 478 AF XY: 0.0592 AC XY: 7814 AN XY: 131896

Gnomad AFR exome AF: 0.00881

Gnomad AMR exome AF: 0.0315

Gnomad ASJ exome AF: 0.0925

Gnomad EAS exome AF: 0.000393

Gnomad SAS exome AF: 0.0880

Gnomad FIN exome AF: 0.0520

Gnomad NFE exome AF: 0.0653

Gnomad OTH exome AF: 0.0663

GnomAD4 exome AF: 0.0606 AC: 87993 AN: 1452780 Hom.: 3083 Cov.: 40 AF XY: 0.0618 AC XY: 44693 AN XY: 722948

Gnomad4 AFR exome AF: 0.00854

Gnomad4 AMR exome AF: 0.0323

Gnomad4 ASJ exome AF: 0.0936

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0865

Gnomad4 FIN exome AF: 0.0520

Gnomad4 NFE exome AF: 0.0629

Gnomad4 OTH exome AF: 0.0607

GnomAD4 genome AF: 0.0470 AC: 7161 AN: 152258 Hom.: 249 Cov.: 33 AF XY: 0.0457 AC XY: 3405 AN XY: 74458

Gnomad4 AFR AF: 0.00946

Gnomad4 AMR AF: 0.0435

Gnomad4 ASJ AF: 0.0916

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0833

Gnomad4 FIN AF: 0.0498

Gnomad4 NFE AF: 0.0669

Gnomad4 OTH AF: 0.0558

Alfa AF: 0.0646 Hom.: 101

Bravo AF: 0.0419

Asia WGS AF: 0.0310 AC: 108 AN: 3478

EpiCase AF: 0.0710

EpiControl AF: 0.0722

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
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 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.7
DANN	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs28365124; hg19: chr16-1260636;