chr19-13317319-A-G

Variant names:

• chr19-13317319-A-G
• rs1308599413
• NM_001127222.2:c.1348T>C

Variant summary

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

The NM_001127222.2(CACNA1A):​c.1348T>C​(p.Ser450Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,445,378 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.44
• 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 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.1348T>C	p.Ser450Pro	missense_variant, splice_region_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.1348T>C	p.Ser450Pro	missense_variant, splice_region_variant	Exon 11 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	Exon 11 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1354T>C	p.Ser452Pro	missense_variant, splice_region_variant	Exon 11 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	Exon 11 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	Exon 11 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	Exon 11 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1210T>C	p.Ser404Pro	missense_variant, splice_region_variant	Exon 10 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	Exon 11 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	Exon 11 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	Exon 11 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1354T>C	p.Ser452Pro	missense_variant, splice_region_variant	Exon 11 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	Exon 11 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	Exon 11 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	Exon 11 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.1351T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 11 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.1348T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 11 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247570 AF XY: 0.00

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: 0.0000466

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445378 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715174

African (AFR) AF: 0.00 AC: 0 AN: 33204

American (AMR) AF: 0.00 AC: 0 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39252

South Asian (SAS) AF: 0.00 AC: 0 AN: 85778

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098392

Other (OTH) AF: 0.00 AC: 0 AN: 59602

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 31, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Vascular dementia Uncertain:1

Apr 01, 2020

Myllykangas group, University of Helsinki

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	2.9	.;.;.;.;M;.;.;M;.;.;.;.;M;.;.
PhyloP100		4.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.024	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.060	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.56
MutPred		0.41		Loss of phosphorylation at S451 (P = 0.0508);.;Loss of phosphorylation at S451 (P = 0.0508);Loss of phosphorylation at S451 (P = 0.0508);Loss of phosphorylation at S451 (P = 0.0508);.;Loss of phosphorylation at S451 (P = 0.0508);Loss of phosphorylation at S451 (P = 0.0508);Loss of phosphorylation at S451 (P = 0.0508);Loss of phosphorylation at S451 (P = 0.0508);Loss of phosphorylation at S451 (P = 0.0508);.;Loss of phosphorylation at S451 (P = 0.0508);.;Loss of phosphorylation at S451 (P = 0.0508);
MVP		0.89
MPC		2.3
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.69
gMVP		0.90
Mutation Taster		=62/38	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: rs1308599413; hg19: chr19-13428133;