NM_001127222.2:c.2374G>T

Variant names:

• chr19-13299259-C-A
• rs753248182
• NM_001127222.2:c.2374G>T

Variant summary

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

The NM_001127222.2(CACNA1A):​c.2374G>T​(p.Ala792Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,050 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A792T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.66
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2374G>T	p.Ala792Ser	missense_variant	Exon 19 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2374G>T	p.Ala792Ser	missense_variant	Exon 19 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2386G>T	p.Ala796Ser	missense_variant	Exon 19 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2380G>T	p.Ala794Ser	missense_variant	Exon 19 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2377G>T	p.Ala793Ser	missense_variant	Exon 19 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2377G>T	p.Ala793Ser	missense_variant	Exon 19 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2377G>T	p.Ala793Ser	missense_variant	Exon 19 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2236G>T	p.Ala746Ser	missense_variant	Exon 18 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2377G>T	p.Ala793Ser	missense_variant	Exon 19 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2386G>T	p.Ala796Ser	missense_variant	Exon 19 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2377G>T	p.Ala793Ser	missense_variant	Exon 19 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2380G>T	p.Ala794Ser	missense_variant	Exon 19 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2377G>T	p.Ala793Ser	missense_variant	Exon 19 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2377G>T	p.Ala793Ser	missense_variant	Exon 19 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2377G>T	p.Ala793Ser	missense_variant	Exon 19 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.2377G>T		non_coding_transcript_exon_variant	Exon 19 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.2374G>T		non_coding_transcript_exon_variant	Exon 19 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000410 AC: 1 AN: 244078 AF XY: 0.00000753

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455050 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 724102

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46840

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111824

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome Cov.: 32

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

May 03, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CACNA1A-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 793 of the CACNA1A protein (p.Ala793Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.065
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	2.0	.;.;.;.;M;.;.;.;.;.;.;.;M;.;.
PhyloP100		7.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.6	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0040	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.18	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.50
MutPred		0.19		.;.;Gain of phosphorylation at A793 (P = 0.0162);Gain of phosphorylation at A793 (P = 0.0162);Gain of phosphorylation at A793 (P = 0.0162);.;Gain of phosphorylation at A793 (P = 0.0162);.;.;Gain of phosphorylation at A793 (P = 0.0162);Gain of phosphorylation at A793 (P = 0.0162);.;Gain of phosphorylation at A793 (P = 0.0162);.;Gain of phosphorylation at A793 (P = 0.0162);
MVP		0.92
MPC		2.0
ClinPred		0.94	D
GERP RS		2.7
Varity_R		0.32
gMVP		0.77
Mutation Taster		=45/55	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: rs753248182; hg19: chr19-13410073;