rs16023

Positions:

• chr19-13298658-T-A
• chr19-13298658-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001127222.2(CACNA1A):​c.2975A>T​(p.Glu992Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,502,488 control chromosomes in the GnomAD database, including 15,900 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E992Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.13 (1408 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14492 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 2.84

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.

• PP2: Missense variant where missense usually causes diseases, CACNA1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017878115).
• BP6: Variant 19-13298658-T-A is Benign according to our data. Variant chr19-13298658-T-A is described in ClinVar as [Benign]. Clinvar id is 68427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298658-T-A is described in Lovd as [Benign]. Variant chr19-13298658-T-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.2975A>T	p.Glu992Val	missense_variant	19/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2975A>T	p.Glu992Val	missense_variant	19/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20277 AN: 151782 Hom.: 1410 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.137 AC: 14100 AN: 102910 Hom.: 1026 AF XY: 0.134 AC XY: 7629 AN XY: 57098

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.0934

Gnomad SAS exome AF: 0.118

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.144 AC: 194404 AN: 1350598 Hom.: 14492 Cov.: 32 AF XY: 0.144 AC XY: 95757 AN XY: 666138

Gnomad4 AFR exome AF: 0.0978

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.163

Gnomad4 EAS exome AF: 0.153

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.121

Gnomad4 NFE exome AF: 0.147

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.133 AC: 20272 AN: 151890 Hom.: 1408 Cov.: 32 AF XY: 0.132 AC XY: 9802 AN XY: 74268

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.148

Alfa AF: 0.145 Hom.: 532

Bravo AF: 0.135

TwinsUK AF: 0.138 AC: 512

ALSPAC AF: 0.146 AC: 563

ESP6500AA AF: 0.0930 AC: 230

ESP6500EA AF: 0.128 AC: 655

ExAC AF: 0.112 AC: 2507

Asia WGS AF: 0.113 AC: 392 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

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	GeneDx	Jan 05, 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	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 30% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 28. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Eurofins Ntd Llc (ga)	Mar 18, 2014	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Mar 11, 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 Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.91
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.69	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationTaster	Benign	0.30	P;P;P
PrimateAI	Pathogenic	0.87	D
Sift4G	Benign	0.16	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.094
MPC		2.0
ClinPred		0.016	T
GERP RS		3.9
Varity_R		0.17
gMVP		0.52

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: rs16023; hg19: chr19-13409472; COSMIC: COSV64201171;