rs16042

Positions:

• chr19-13230223-G-A
• chr19-13230223-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127222.2(CACNA1A):​c.5401-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,612,806 control chromosomes in the GnomAD database, including 26,312 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3028 hom., cov: 31)
  • Exomes 𝑓: 0.15 (23284 hom.)
• Consequence: CACNA1A NM_001127222.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.181

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

CACNA1A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-13230223-G-A is Benign according to our data. Variant chr19-13230223-G-A is described in ClinVar as [Benign]. Clinvar id is 257511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13230223-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5401-14C>T		intron_variant		ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5401-14C>T		intron_variant		1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5419-14C>T		intron_variant		5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5407-14C>T		intron_variant		5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5404-14C>T		intron_variant		5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5404-14C>T		intron_variant		1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5404-14C>T		intron_variant		5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5263-14C>T		intron_variant		5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5404-14C>T		intron_variant		5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5419-14C>T		intron_variant		5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5410-14C>T		intron_variant		5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5407-14C>T		intron_variant		5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5404-14C>T		intron_variant		5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5404-14C>T		intron_variant		1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5404-14C>T		intron_variant		5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.28-14C>T		intron_variant		5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26050 AN: 151874 Hom.: 3031 Cov.: 31

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.645

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.0941

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.168

GnomAD3 exomes AF: 0.200 AC: 49551 AN: 248370 Hom.: 7404 AF XY: 0.195 AC XY: 26274 AN XY: 134810

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.277

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.642

Gnomad SAS exome AF: 0.231

Gnomad FIN exome AF: 0.0991

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.163

GnomAD4 exome AF: 0.154 AC: 225038 AN: 1460814 Hom.: 23284 Cov.: 32 AF XY: 0.155 AC XY: 112813 AN XY: 726716

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.273

Gnomad4 ASJ exome AF: 0.132

Gnomad4 EAS exome AF: 0.610

Gnomad4 SAS exome AF: 0.230

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.171 AC: 26060 AN: 151992 Hom.: 3028 Cov.: 31 AF XY: 0.176 AC XY: 13066 AN XY: 74270

Gnomad4 AFR AF: 0.176

Gnomad4 AMR AF: 0.230

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.645

Gnomad4 SAS AF: 0.248

Gnomad4 FIN AF: 0.0941

Gnomad4 NFE AF: 0.129

Gnomad4 OTH AF: 0.168

Alfa AF: 0.142 Hom.: 3639

Bravo AF: 0.185

Asia WGS AF: 0.411 AC: 1426 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 42% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 39. Only high quality variants are reported. -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.0
DANN	Benign	0.74

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: rs16042; hg19: chr19-13341037; COSMIC: COSV64213397; COSMIC: COSV64213397;