rs121908235

chr19-13209438-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BS1_Supporting BS2

The NM_001127222.2(CACNA1A):c.6400C>T(p.Arg2134Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,383,484 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2134H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10 B:1 O:1
• Conservation: PhyloP100: 2.67

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CACNA1A
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000119 (147/1231192) while in subpopulation MID AF= 0.00109 (5/4598). AF 95% confidence interval is 0.000428. There are 1 homozygotes in gnomad4_exome. There are 71 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.6400C>T	p.Arg2134Cys	missense_variant	45/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6400C>T	p.Arg2134Cys	missense_variant	45/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000451 AC: 3 AN: 66538 Hom.: 0 AF XY: 0.0000575 AC XY: 2 AN XY: 34754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000984

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 147 AN: 1231192 Hom.: 1 Cov.: 32 AF XY: 0.000120 AC XY: 71 AN XY: 593754

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000322

Gnomad4 SAS exome AF: 0.0000207

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.000120

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74460

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.000366 AC: 3

ExAC AF: 0.0000442 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:10 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 07, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2023	Reported in an individual with episodic ataxia (Mantuano et al., 2004) and an individual with small vessel disease-related stroke (Tan et al., 2019); also reported in an individual with cognitive impairment, behavior disorder, hypophonia and dysarthria (Mariani et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15173248, 34426522, 31719132, 27400454, 35401678, 28252636) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CACNA1A: PP2, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 21, 2021	- -

Episodic ataxia type 2 Uncertain:1 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 18, 2020	The heterozygous p.Arg2135Cys (also known as p.Arg2136Cys) missense variant identified in CACNA1A has been reported in a patient with episodic ataxia type 2 [PMID: 15173248], and in another individual with developmental delay and spastic diplegia who inherited the variant from asymptomatic father [PMID: 28252636]. The variant has 0.00005107 allele frequency in the gnomAD database (5 out of 97,896 heterozygous alleles) indicating it is a rare allele in the general population. The affected reside is moderately conserved and in silico tools provide conflicting interpretations about pathogenicity of this variant. Functional studies to evaluate the potential pathogenicy of this variant have not been performed to the best of our knowledge. Based on the available evidence, the p.Arg2135Cys variant in the CACNA1A gene is classified as a variant of uncertain significance. -

Tip-toe gait Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Jan 11, 2022

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 07, 2023

Variant summary: CACNA1A c.6403C>T (p.Arg2135Cys) results in a non-conservative amino acid change located in the C-terminal tail, upstream of the polyglutamine repeat (Mantuano_2004). The CACNA1A gene has a bicistronic mRNA, with the first cistron encoding the voltage-gated calcium channel subunit alpha1A and the second cistron expressing the C-terminal fragment of the alpha1A subunit (alpha1ACT), which is a transcription factor (that also contains the polyglutamine tract), and coordinates the expression of genes involved in neural and Purkinje cell development (PMID: 23827678); our variant of interest affects both of these encoded proteins. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.3e-05 (i.e. in 11 carriers) in 150946 control chromosomes (gnomAD v3.1, genomes dataset). The variant, c.6403C>T, has also been reported in the literature in heterozygous individuals affected with Episodic ataxia type 2 (Mantuano_2004), Huntington disease-like phenotype (Mariani_2016), small vessel disease-related lacunar stroke (Tan_2019), and spinocerebellar ataxia (Ghorbani_2022). In addition, the variant was also reported in an exome study in a child with developmental delay and spastic diplegia, however the variant was inherited from an asymptomatic father (Baldridge_2017). These reports do not provide unequivocal conclusions about association of the variant with Episodic ataxia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, partly without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Spinocerebellar ataxia type 6 Uncertain:1

Uncertain significance, no assertion criteria provided

research

O&I group, Department of Genetics, University Medical Center of Groningen

Jul 22, 2021

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2018

The p.R2135C variant (also known as c.6403C>T), located in coding exon 45 of the CACNA1A gene, results from a C to T substitution at nucleotide position 6403. The arginine at codon 2135 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in two individuals in the literature; one with a clinical diagnosis of episodic ataxia type 2 (EA2) and another with Huntingon Disease symptoms who eventually developed cerebellar signs and dysarthria. Of note, this alteration has been called p.R2136C (c.6681C>T) and p.R2140C (c.6418C>T) in the literature (Mantuano E et al. J. Med. Genet., 2004 Jun;41:e82; Mariani LL et al. JAMA Neurol, 2016 Sep;73:1105-14). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Cerebellar ataxia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Nov 22, 2018

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	0.045
Eigen_PC	Benign	-0.026
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Pathogenic	0.83	D
Sift4G	Uncertain	0.0080	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.86
MVP		0.96
MPC		0.39
ClinPred		0.36	T
GERP RS		2.5
Varity_R		0.12
gMVP		0.33

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: rs121908235; hg19: chr19-13320252;