19-13286647-G-T

Variant names:

• chr19-13286647-G-T
• rs199793367
• NM_001127222.2:c.3409C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001127222.2(CACNA1A):​c.3409C>A​(p.Pro1137Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000719 in 1,391,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P1137L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.35
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2862486).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127222.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	NM_001127222.2	MANE Select	c.3409C>A	p.Pro1137Thr	missense	Exon 20 of 47	NP_001120694.1
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.3412C>A	p.Pro1138Thr	missense	Exon 20 of 47	NP_001120693.1
	CACNA1A	NM_023035.3		c.3421C>A	p.Pro1141Thr	missense	Exon 20 of 48	NP_075461.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.3409C>A	p.Pro1137Thr	missense	Exon 20 of 47	ENSP00000353362.5
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.3412C>A	p.Pro1138Thr	missense	Exon 20 of 47	ENSP00000489913.1
	CACNA1A	ENST00000638029.1	TSL:5	c.3421C>A	p.Pro1141Thr	missense	Exon 20 of 48	ENSP00000489829.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391288 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 684574

African (AFR) AF: 0.00 AC: 0 AN: 31232

American (AMR) AF: 0.00 AC: 0 AN: 35136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21398

East Asian (EAS) AF: 0.00 AC: 0 AN: 38998

South Asian (SAS) AF: 0.00 AC: 0 AN: 75326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5374

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076832

Other (OTH) AF: 0.00 AC: 0 AN: 57286

GnomAD4 genome Cov.: 30

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

Jul 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1138 of the CACNA1A protein (p.Pro1138Thr). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1A protein function. 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

Oct 09, 2024

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.4	L
PhyloP100		5.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.018	D
Sift4G	Benign	0.14	T
Vest4		0.43
MutPred		0.18		Loss of catalytic residue at P1137 (P = 0.0194)
MVP		0.83
MPC		0.091
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.19
gMVP		0.55
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: rs199793367; hg19: chr19-13397461;