rs16012

Positions:

• chr19-13308421-G-C

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.1776C>G​(p.Val592=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,609,264 control chromosomes in the GnomAD database, including 358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (17 hom., cov: 31)
  • Exomes 𝑓: 0.019 (341 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.24

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=-0.38).
• BP6: Variant 19-13308421-G-C is Benign according to our data. Variant chr19-13308421-G-C is described in ClinVar as [Benign]. Clinvar id is 128545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13308421-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0118 (1799/152154) while in subpopulation NFE AF= 0.0208 (1417/68002). AF 95% confidence interval is 0.0199. There are 17 homozygotes in gnomad4. There are 802 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1799 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.1776C>G	p.Val592=	synonymous_variant	13/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1776C>G	p.Val592=	synonymous_variant	13/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1799 AN: 152036 Hom.: 17 Cov.: 31

Gnomad AFR AF: 0.00324

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.0113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00822

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0208

Gnomad OTH AF: 0.00862

GnomAD3 exomes AF: 0.0112 AC: 2756 AN: 247170 Hom.: 23 AF XY: 0.0111 AC XY: 1493 AN XY: 134040

Gnomad AFR exome AF: 0.00331

Gnomad AMR exome AF: 0.00481

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00223

Gnomad FIN exome AF: 0.00801

Gnomad NFE exome AF: 0.0191

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0186 AC: 27112 AN: 1457110 Hom.: 341 Cov.: 31 AF XY: 0.0181 AC XY: 13100 AN XY: 724848

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.00512

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00238

Gnomad4 FIN exome AF: 0.00859

Gnomad4 NFE exome AF: 0.0225

Gnomad4 OTH exome AF: 0.0145

GnomAD4 genome AF: 0.0118 AC: 1799 AN: 152154 Hom.: 17 Cov.: 31 AF XY: 0.0108 AC XY: 802 AN XY: 74386

Gnomad4 AFR AF: 0.00323

Gnomad4 AMR AF: 0.00576

Gnomad4 ASJ AF: 0.0113

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00822

Gnomad4 NFE AF: 0.0208

Gnomad4 OTH AF: 0.00853

Alfa AF: 0.0164 Hom.: 2

Bravo AF: 0.0114

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 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. -

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

Jun 18, 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. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Benign	0.86

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: rs16012; hg19: chr19-13419235;