rs755172189

Variant names:

• chr19-13255180-C-T
• rs755172189
• NM_001127222.2:c.4670G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PP2 PP3_Moderate BS2

The NM_001127222.2(CACNA1A):​c.4670G>A​(p.Arg1557His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,676 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.20

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a repeat IV (size 263) in uniprot entity CAC1A_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_001127222.2
• PP2: Missense variant in the CACNA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. Gene score misZ: 5.7845 (above the threshold of 3.09). Trascript score misZ: 3.9354 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4670G>A	p.Arg1557His	missense_variant	Exon 29 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4670G>A	p.Arg1557His	missense_variant	Exon 29 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4682G>A	p.Arg1561His	missense_variant	Exon 29 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4676G>A	p.Arg1559His	missense_variant	Exon 29 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4673G>A	p.Arg1558His	missense_variant	Exon 29 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4673G>A	p.Arg1558His	missense_variant	Exon 29 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4673G>A	p.Arg1558His	missense_variant	Exon 29 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4532G>A	p.Arg1511His	missense_variant	Exon 28 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4673G>A	p.Arg1558His	missense_variant	Exon 29 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4682G>A	p.Arg1561His	missense_variant	Exon 29 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4673G>A	p.Arg1558His	missense_variant	Exon 29 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4676G>A	p.Arg1559His	missense_variant	Exon 29 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4673G>A	p.Arg1558His	missense_variant	Exon 29 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4673G>A	p.Arg1558His	missense_variant	Exon 29 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4673G>A	p.Arg1558His	missense_variant	Exon 29 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249126 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135138

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461568 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74306

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Sep 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1558 of the CACNA1A protein (p.Arg1558His). This variant is present in population databases (rs755172189, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 542832). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. -

Inborn genetic diseases Uncertain:1

Jan 31, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1558H variant (also known as c.4673G>A), located in coding exon 29 of the CACNA1A gene, results from a G to A substitution at nucleotide position 4673. The arginine at codon 1558 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1

Jan 05, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;.;T;.;.;.;.;.;.;.;T;.;.;.;T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.7	.;.;.;.;L;.;.;.;.;.;.;.;.;L;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.3	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.73
Sift	Benign	0.038	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.071	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.65
MutPred		0.62		.;.;Loss of MoRF binding (P = 0.0151);Loss of MoRF binding (P = 0.0151);Loss of MoRF binding (P = 0.0151);.;.;Loss of MoRF binding (P = 0.0151);.;.;Loss of MoRF binding (P = 0.0151);Loss of MoRF binding (P = 0.0151);.;Loss of MoRF binding (P = 0.0151);.;Loss of MoRF binding (P = 0.0151);.;
MVP		0.91
MPC		1.6
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.32
gMVP		0.86

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: rs755172189; hg19: chr19-13365994;