rs121908235

Variant names:

• chr19-13209438-G-A
• rs121908235
• NM_001127222.2:c.6400C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. 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 Likely benign.

• 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
• Publications: 5 publications found

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]

CACNA1A Gene-Disease associations (from GenCC):

• episodic ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• developmental and epileptic encephalopathy, 42

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• migraine, familial hemiplegic, 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• benign paroxysmal torticollis of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300728 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 71 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6400C>T	p.Arg2134Cys	missense_variant	Exon 45 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6400C>T	p.Arg2134Cys	missense_variant	Exon 45 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6418C>T	p.Arg2140Cys	missense_variant	Exon 46 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6406C>T	p.Arg2136Cys	missense_variant	Exon 45 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6403C>T	p.Arg2135Cys	missense_variant	Exon 45 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6403C>T	p.Arg2135Cys	missense_variant	Exon 45 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6367C>T	p.Arg2123Cys	missense_variant	Exon 44 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6262C>T	p.Arg2088Cys	missense_variant	Exon 44 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6403C>T	p.Arg2135Cys	missense_variant	Exon 45 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6418C>T	p.Arg2140Cys	missense_variant	Exon 46 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6409C>T	p.Arg2137Cys	missense_variant	Exon 46 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6406C>T	p.Arg2136Cys	missense_variant	Exon 45 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6403C>T	p.Arg2135Cys	missense_variant	Exon 45 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6403C>T	p.Arg2135Cys	missense_variant	Exon 45 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6367C>T	p.Arg2123Cys	missense_variant	Exon 44 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.*666C>T		non_coding_transcript_exon_variant	Exon 43 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*1579C>T		non_coding_transcript_exon_variant	Exon 45 of 47			ENSP00000519091.1
CACNA1A	ENST00000636768.2	n.*666C>T		3_prime_UTR_variant	Exon 43 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*1579C>T		3_prime_UTR_variant	Exon 45 of 47			ENSP00000519091.1

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

GnomAD2 exomes AF: 0.0000451 AC: 3 AN: 66538 AF XY: 0.0000575

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 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

African (AFR) AF: 0.00 AC: 0 AN: 25744

American (AMR) AF: 0.00 AC: 0 AN: 15400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16816

East Asian (EAS) AF: 0.0000322 AC: 1 AN: 31060

South Asian (SAS) AF: 0.0000207 AC: 1 AN: 48312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43016

Middle Eastern (MID) AF: 0.00109 AC: 5 AN: 4598

European-Non Finnish (NFE) AF: 0.000135 AC: 134 AN: 996248

Other (OTH) AF: 0.000120 AC: 6 AN: 49998

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000158 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

Feb 14, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 21, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 08, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in an individual with episodic ataxia and an individual with small vessel disease-related stroke; also reported in an individual with cognitive impairment, behavior disorder, hypophonia and dysarthria (PMID: 31719132, 15173248, 27400454); 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, 35401678, 28252636, 27400454, 37091313, 38374194) -

Nov 07, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1A: PP2, PP3 -

Episodic ataxia type 2 Uncertain:1 Other:1

Apr 18, 2020

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Tip-toe gait Pathogenic:1

Jan 11, 2022

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

not specified Uncertain:1

Feb 07, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 22, 2021

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Inborn genetic diseases Uncertain:1

May 31, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 22, 2018

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DEOGEN2	Benign	0.26	.;T;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
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
MutationAssessor	Uncertain	2.3	.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		2.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.9	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.012	.;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
Mutation Taster		=8/92	disease causing

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

Other links and lift over

dbSNP: rs121908235; hg19: chr19-13320252;