19-13230158-G-C

Variant names:

• chr19-13230158-G-C
• rs267606696
• NM_001127222.2:c.5452C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001127222.2(CACNA1A):​c.5452C>G​(p.Arg1818Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1818P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43
• Publications: 3 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5452C>G	p.Arg1818Gly	missense_variant	Exon 36 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2	c.5455C>G	p.Arg1819Gly	missense_variant	Exon 36 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5452C>G	p.Arg1818Gly	missense_variant	Exon 36 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2	c.5455C>G	p.Arg1819Gly	missense_variant	Exon 36 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1	c.5470C>G	p.Arg1824Gly	missense_variant	Exon 37 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5458C>G	p.Arg1820Gly	missense_variant	Exon 36 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5455C>G	p.Arg1819Gly	missense_variant	Exon 36 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5455C>G	p.Arg1819Gly	missense_variant	Exon 36 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5455C>G	p.Arg1819Gly	missense_variant	Exon 36 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5314C>G	p.Arg1772Gly	missense_variant	Exon 35 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5455C>G	p.Arg1819Gly	missense_variant	Exon 36 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5470C>G	p.Arg1824Gly	missense_variant	Exon 37 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5461C>G	p.Arg1821Gly	missense_variant	Exon 37 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5458C>G	p.Arg1820Gly	missense_variant	Exon 36 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5455C>G	p.Arg1819Gly	missense_variant	Exon 36 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1	c.5455C>G	p.Arg1819Gly	missense_variant	Exon 36 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.5455C>G		non_coding_transcript_exon_variant	Exon 36 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*633C>G		non_coding_transcript_exon_variant	Exon 37 of 47			ENSP00000519091.1
CACNA1A	ENST00000713789.1	n.*633C>G		3_prime_UTR_variant	Exon 37 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249208 AF XY: 0.00000740

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461682 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727128

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111848

Other (OTH) AF: 0.00 AC: 0 AN: 60372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Sep 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with glycine at codon 1819 of the CACNA1A protein (p.Arg1819Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs267606696, ExAC 0.002%). This variant has not been reported in the literature in individuals with CACNA1A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;T;.;.;.;.;.;D;.;.;T;.;.;.;T;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.0	.;.;.;.;H;.;.;.;.;.;.;.;.;.;H;.;.;.
PhyloP100		2.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.83
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.91
gMVP		0.97
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs267606696; hg19: chr19-13340972;