19-13235702-C-T

Variant names:

• chr19-13235702-C-T
• rs121908216
• NM_001127222.2:c.4979G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1660C) has been classified 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
• Publications: 12 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: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-13235703-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1308366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 8495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4979G>A	p.Arg1660His	missense_variant	Exon 32 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4979G>A	p.Arg1660His	missense_variant	Exon 32 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4997G>A	p.Arg1666His	missense_variant	Exon 33 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4985G>A	p.Arg1662His	missense_variant	Exon 32 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4982G>A	p.Arg1661His	missense_variant	Exon 32 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4982G>A	p.Arg1661His	missense_variant	Exon 32 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4982G>A	p.Arg1661His	missense_variant	Exon 32 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4841G>A	p.Arg1614His	missense_variant	Exon 31 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4982G>A	p.Arg1661His	missense_variant	Exon 32 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4997G>A	p.Arg1666His	missense_variant	Exon 33 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4988G>A	p.Arg1663His	missense_variant	Exon 33 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4985G>A	p.Arg1662His	missense_variant	Exon 32 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4982G>A	p.Arg1661His	missense_variant	Exon 32 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4982G>A	p.Arg1661His	missense_variant	Exon 32 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4982G>A	p.Arg1661His	missense_variant	Exon 32 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.4982G>A		non_coding_transcript_exon_variant	Exon 32 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*160G>A		non_coding_transcript_exon_variant	Exon 33 of 47			ENSP00000519091.1
CACNA1A	ENST00000713789.1	n.*160G>A		3_prime_UTR_variant	Exon 33 of 47			ENSP00000519091.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111698

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000418 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

Feb 16, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 01, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1A: PP1:Strong, PM1, PM2, PS4:Moderate, PP2 -

Oct 29, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant segregates with episodic ataxia in at least one family and has been identified in multiple unrelated individuals with cerebellar ataxia. In some published literature, this variant is referred to as Arg1666His, Arg1660His or Arg1661His. Computational tools predict that this variant is damaging. -

Mar 20, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 37273706, 11814735, 26814174, 28742085, 34507393, 29482223, 34758253, 35401678, 34806130, 10987655) -

Nov 07, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PP3, PM2_moderate, PS4_moderate -

Episodic ataxia type 2 Pathogenic:2 Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 23, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Spinocerebellar ataxia type 6 Pathogenic:2

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

O&I group, Department of Genetics, University Medical Center of Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

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 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). 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) 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;.;.;.;.;.
PhyloP100		4.1
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
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs121908216; hg19: chr19-13346516;