rs16029

chr19-13286510-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001127222.2(CACNA1A):c.3546C>T(p.Val1182=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,368,834 control chromosomes in the GnomAD database, including 341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (36 hom., cov: 30)
  • Exomes 𝑓: 0.020 (305 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.594

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 19-13286510-G-A is Benign according to our data. Variant chr19-13286510-G-A is described in ClinVar as [Benign]. Clinvar id is 93561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13286510-G-A is described in Lovd as [Benign]. Variant chr19-13286510-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.594 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0173 (2612/151270) while in subpopulation NFE AF= 0.0274 (1857/67692). AF 95% confidence interval is 0.0264. There are 36 homozygotes in gnomad4. There are 1274 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2611 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.3546C>T	p.Val1182=	synonymous_variant	20/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3546C>T	p.Val1182=	synonymous_variant	20/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2611 AN: 151146 Hom.: 36 Cov.: 30

Gnomad AFR AF: 0.00373

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.00998

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.000392

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.0244

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0274

Gnomad OTH AF: 0.0154

GnomAD3 exomes AF: 0.0170 AC: 2890 AN: 169562 Hom.: 30 AF XY: 0.0178 AC XY: 1599 AN XY: 89896

Gnomad AFR exome AF: 0.00417

Gnomad AMR exome AF: 0.00916

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.000134

Gnomad SAS exome AF: 0.0109

Gnomad FIN exome AF: 0.0256

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0196 AC: 23841 AN: 1217564 Hom.: 305 Cov.: 19 AF XY: 0.0197 AC XY: 11884 AN XY: 603788

Gnomad4 AFR exome AF: 0.00323

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0146

Gnomad4 EAS exome AF: 0.000135

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.0276

Gnomad4 NFE exome AF: 0.0214

Gnomad4 OTH exome AF: 0.0180

GnomAD4 genome AF: 0.0173 AC: 2612 AN: 151270 Hom.: 36 Cov.: 30 AF XY: 0.0172 AC XY: 1274 AN XY: 73914

Gnomad4 AFR AF: 0.00372

Gnomad4 AMR AF: 0.00997

Gnomad4 ASJ AF: 0.0188

Gnomad4 EAS AF: 0.000392

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.0244

Gnomad4 NFE AF: 0.0274

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0221 Hom.: 33

Bravo AF: 0.0143

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 12, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 31, 2017

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	1.3
Dann	Benign	0.69

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: rs16029; hg19: chr19-13397324; COSMIC: COSV64190077; COSMIC: COSV64190077;