rs121908216

Positions:

• chr19-13235702-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001127222.2(CACNA1A):​c.4979G>A​(p.Arg1660His) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,470 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 4.10

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S4 of repeat IV (size 18) in uniprot entity CAC1A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 19-13235702-C-T is Pathogenic according to our data. Variant chr19-13235702-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13235702-C-T is described in Lovd as [Pathogenic]. Variant chr19-13235702-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4979G>A	p.Arg1660His	missense_variant	32/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4979G>A	p.Arg1660His	missense_variant	32/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4997G>A	p.Arg1666His	missense_variant	33/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4985G>A	p.Arg1662His	missense_variant	32/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4982G>A	p.Arg1661His	missense_variant	32/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4982G>A	p.Arg1661His	missense_variant	32/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4982G>A	p.Arg1661His	missense_variant	32/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4841G>A	p.Arg1614His	missense_variant	31/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4982G>A	p.Arg1661His	missense_variant	32/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4997G>A	p.Arg1666His	missense_variant	33/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4988G>A	p.Arg1663His	missense_variant	33/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4985G>A	p.Arg1662His	missense_variant	32/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4982G>A	p.Arg1661His	missense_variant	32/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4982G>A	p.Arg1661His	missense_variant	32/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4982G>A	p.Arg1661His	missense_variant	32/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461470 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727028

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 16, 2021	DNA sequence analysis of the CACNA1A gene demonstrated a sequence change, c.4982G>A, in exon 32 that results in an amino acid change, p.Arg1661His. This sequence change has not been described in the gnomAD general population database. This sequence change has been described in a family with episodic ataxia type 2 and familial hemiplegic migraine, and was shown to co-segregate with the disease phenotype (PMID: 10987655). The p.Arg1661His change affects a highly conserved amino acid residue located in the S4 transmembrane segment of domain IV of the CACNA1A protein. It appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Collectively these evidences suggests this p.Arg1661His variant is likely pathogenic, however functional studies have not been performed to prove this conclusively. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2022	This variant segregates with episodic ataxia in one family (PMID: 10987655) and is also reported in an unrelated individual with pure cerebellar ataxia (PMID: 29482223). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as Arg1666His or Arg1660His. Computational tools predict that this variant is damaging. -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16325861, 11179022, 11814735, 26814174, 28742085, 34507393, 29482223, 34758253, 10987655, 35401678, 34806130) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 07, 2023	PP2, PP3, PM2_moderate, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CACNA1A: PP1:Strong, PM1, PM2, PS4:Moderate, PP2 -

Episodic ataxia type 2 Pathogenic:2 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1999	- -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Oct 23, 2018	- -

Spinocerebellar ataxia type 6 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Likely pathogenic, no assertion criteria provided	research	O&I group, Department of Genetics, University Medical Center of Groningen	Jul 22, 2021	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1661 of the CACNA1A protein (p.Arg1661His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of, or diagnosis of, episodic ataxia (PMID: 10987655, 29482223). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg1666His. ClinVar contains an entry for this variant (Variation ID: 8495). 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 expected to disrupt CACNA1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	.;.;T;.;.;.;.;.;D;.;.;T;.;.;.;T;.;.;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	5.2	.;.;.;.;H;.;.;.;.;.;.;.;.;.;H;.;.;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.66
MutPred		0.82		.;.;Loss of methylation at R1661 (P = 0.0171);Loss of methylation at R1661 (P = 0.0171);Loss of methylation at R1661 (P = 0.0171);.;.;Loss of methylation at R1661 (P = 0.0171);.;.;.;Loss of methylation at R1661 (P = 0.0171);Loss of methylation at R1661 (P = 0.0171);.;Loss of methylation at R1661 (P = 0.0171);.;.;.;.;.;
MVP		0.98
MPC		1.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.77
gMVP		0.98

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: rs121908216; hg19: chr19-13346516;