rs16016

chr19-13303780-C-T

Variant summary

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

The NM_001127222.2(CACNA1A):c.2091G>A(p.Thr697=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,608,958 control chromosomes in the GnomAD database, including 18,209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1447 hom., cov: 29)
  • Exomes 𝑓: 0.14 (16762 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.00

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-13303780-C-T is Benign according to our data. Variant chr19-13303780-C-T is described in ClinVar as [Benign]. Clinvar id is 128546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13303780-C-T is described in Lovd as [Benign]. Variant chr19-13303780-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.2091G>A	p.Thr697=	synonymous_variant	16/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2091G>A	p.Thr697=	synonymous_variant	16/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19329 AN: 151852 Hom.: 1441 Cov.: 29

Gnomad AFR AF: 0.0832

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.165 AC: 41049 AN: 249262 Hom.: 3997 AF XY: 0.167 AC XY: 22603 AN XY: 135228

Gnomad AFR exome AF: 0.0814

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.304

Gnomad SAS exome AF: 0.259

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.143 AC: 207901 AN: 1456986 Hom.: 16762 Cov.: 31 AF XY: 0.146 AC XY: 105703 AN XY: 725134

Gnomad4 AFR exome AF: 0.0829

Gnomad4 AMR exome AF: 0.220

Gnomad4 ASJ exome AF: 0.136

Gnomad4 EAS exome AF: 0.302

Gnomad4 SAS exome AF: 0.258

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.127 AC: 19358 AN: 151972 Hom.: 1447 Cov.: 29 AF XY: 0.130 AC XY: 9675 AN XY: 74260

Gnomad4 AFR AF: 0.0834

Gnomad4 AMR AF: 0.166

Gnomad4 ASJ AF: 0.127

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.267

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.137

Alfa AF: 0.130 Hom.: 2233

Bravo AF: 0.130

Asia WGS AF: 0.331 AC: 1148 AN: 3478

EpiCase AF: 0.124

EpiControl AF: 0.123

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 08, 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. -
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, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2021	- -
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	-	- -

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

Feb 09, 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	-0.84
Cadd	Benign	0.24
Dann	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs16016; hg19: chr19-13414594; COSMIC: COSV64192873; COSMIC: COSV64192873;