rs187259531

Positions:

• chr19-13332899-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM1 PP2 BP4_Moderate BS1_Supporting BS2

The NM_001127222.2(CACNA1A):​c.1225A>C​(p.Thr409Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,612,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 2.37

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a modified_residue Phosphothreonine (size 0) in uniprot entity CAC1A_HUMAN
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1595388).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000788 (12/152204) while in subpopulation AMR AF= 0.00072 (11/15282). AF 95% confidence interval is 0.000403. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.1225A>C	p.Thr409Pro	missense_variant	9/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1225A>C	p.Thr409Pro	missense_variant	9/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1225A>C	p.Thr409Pro	missense_variant	9/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1225A>C	p.Thr409Pro	missense_variant	9/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1225A>C	p.Thr409Pro	missense_variant	9/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1225A>C	p.Thr409Pro	missense_variant	9/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1225A>C	p.Thr409Pro	missense_variant	9/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1084A>C	p.Thr362Pro	missense_variant	8/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1225A>C	p.Thr409Pro	missense_variant	9/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1225A>C	p.Thr409Pro	missense_variant	9/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1225A>C	p.Thr409Pro	missense_variant	9/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1225A>C	p.Thr409Pro	missense_variant	9/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1225A>C	p.Thr409Pro	missense_variant	9/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1225A>C	p.Thr409Pro	missense_variant	9/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1225A>C	p.Thr409Pro	missense_variant	9/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248274 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134710

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460768 Hom.: 0 Cov.: 29 AF XY: 0.00000826 AC XY: 6 AN XY: 726698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152204 Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5 AN XY: 74422

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000219

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 16, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2024	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.1225A>C (p.T409P) alteration is located in exon 9 (coding exon 9) of the CACNA1A gene. This alteration results from a A to C substitution at nucleotide position 1225, causing the threonine (T) at amino acid position 409 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

CACNA1A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.32	.;T;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.70	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.53	.;N;.;.;N;.;.;N;.;.;.;.;N;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.044	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.14	T;T;.;.;.;.;.;.;.;.;.;T;.;.;.
Polyphen		0.63	.;P;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.41
MVP		0.90
MPC		2.5
ClinPred		0.50	D
GERP RS		4.3
Varity_R		0.53
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs187259531; hg19: chr19-13443713;