rs375210532

Variant names:

• chr19-13317133-C-G
• rs375210532
• NM_001127222.2:c.1534G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-13317133-C-G
• chr19-13317133-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001127222.2(CACNA1A):​c.1534G>C​(p.Glu512Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E512K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.33
• Publications: 0 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

ENSG00000306107 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17462322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.1534G>C	p.Glu512Gln	missense_variant	Exon 11 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1534G>C	p.Glu512Gln	missense_variant	Exon 11 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1537G>C	p.Glu513Gln	missense_variant	Exon 11 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1540G>C	p.Glu514Gln	missense_variant	Exon 11 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1537G>C	p.Glu513Gln	missense_variant	Exon 11 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1537G>C	p.Glu513Gln	missense_variant	Exon 11 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1537G>C	p.Glu513Gln	missense_variant	Exon 11 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1396G>C	p.Glu466Gln	missense_variant	Exon 10 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1537G>C	p.Glu513Gln	missense_variant	Exon 11 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1537G>C	p.Glu513Gln	missense_variant	Exon 11 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1537G>C	p.Glu513Gln	missense_variant	Exon 11 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1540G>C	p.Glu514Gln	missense_variant	Exon 11 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1537G>C	p.Glu513Gln	missense_variant	Exon 11 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1537G>C	p.Glu513Gln	missense_variant	Exon 11 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1537G>C	p.Glu513Gln	missense_variant	Exon 11 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.1537G>C		non_coding_transcript_exon_variant	Exon 11 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.1534G>C		non_coding_transcript_exon_variant	Exon 11 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454694 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722140

African (AFR) AF: 0.00 AC: 0 AN: 33328

American (AMR) AF: 0.00 AC: 0 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.00 AC: 0 AN: 86010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1106124

Other (OTH) AF: 0.0000167 AC: 1 AN: 60058

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 513 of the CACNA1A protein (p.Glu513Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 570501). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CACNA1A protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Dec 04, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.014	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.79	.;.;.;.;N;.;.;N;.;.;.;.;N;.;.
PhyloP100		3.3
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.7	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.80	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.65	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.25
MutPred		0.42		Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);
MVP		0.81
MPC		1.8
ClinPred		0.38	T
GERP RS		3.8
Varity_R		0.16
gMVP		0.56
Mutation Taster		=94/6	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: rs375210532; hg19: chr19-13427947;