rs187393245

Variant names:

• chr19-13286890-G-A
• rs187393245
• NM_001127222.2:c.3166C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001127222.2(CACNA1A):​c.3166C>T​(p.Arg1056Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000341 in 1,613,484 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. R1056H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00036 (8 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.45
• 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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019113302).
• BP6: Variant 19-13286890-G-A is Benign according to our data. Variant chr19-13286890-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 385634.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000204 (31/152312) while in subpopulation EAS AF = 0.0058 (30/5176). AF 95% confidence interval is 0.00417. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3166C>T	p.Arg1056Cys	missense_variant	Exon 20 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3166C>T	p.Arg1056Cys	missense_variant	Exon 20 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3178C>T	p.Arg1060Cys	missense_variant	Exon 20 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3172C>T	p.Arg1058Cys	missense_variant	Exon 20 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3169C>T	p.Arg1057Cys	missense_variant	Exon 20 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3169C>T	p.Arg1057Cys	missense_variant	Exon 20 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3169C>T	p.Arg1057Cys	missense_variant	Exon 20 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3028C>T	p.Arg1010Cys	missense_variant	Exon 19 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3169C>T	p.Arg1057Cys	missense_variant	Exon 20 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3178C>T	p.Arg1060Cys	missense_variant	Exon 20 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3169C>T	p.Arg1057Cys	missense_variant	Exon 20 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3172C>T	p.Arg1058Cys	missense_variant	Exon 20 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3169C>T	p.Arg1057Cys	missense_variant	Exon 20 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3169C>T	p.Arg1057Cys	missense_variant	Exon 20 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3169C>T	p.Arg1057Cys	missense_variant	Exon 20 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.3169C>T		non_coding_transcript_exon_variant	Exon 20 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.3166C>T		non_coding_transcript_exon_variant	Exon 20 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152194 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000269 AC: 66 AN: 245698 AF XY: 0.000224

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00363

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000355 AC: 519 AN: 1461172 Hom.: 8 Cov.: 35 AF XY: 0.000334 AC XY: 243 AN XY: 726874

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0123 AC: 489 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111822

Other (OTH) AF: 0.000133 AC: 8 AN: 60360

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152312 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16 AN XY: 74474

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00580 AC: 30 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000314 Hom.: 2

Bravo AF: 0.0000680

ExAC AF: 0.000333 AC: 40

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Apr 29, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the CACNA1A gene. The R1057C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The 1000 Genomes Project reports R1057C was observed in 4/208 (2.0%) alleles from individuals of Japanese background, indicating it may be a rare (benign) variant in this population. The R1057C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in Human Gene Mutation Database in association with CACNA1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Inborn genetic diseases Uncertain:1

Jun 07, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1057C variant (also known as c.3169C>T), located in coding exon 20 of the CACNA1A gene, results from a C to T substitution at nucleotide position 3169. The arginine at codon 1057 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.019	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.7	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PhyloP100		5.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.1	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0050	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.020	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.74
MVP		0.91
MPC		0.022
ClinPred		0.19	T
GERP RS		5.2
Varity_R		0.20
gMVP		0.54
Mutation Taster		=73/27	polymorphism

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: rs187393245; hg19: chr19-13397704;