rs121908220

Variant names:

• chr19-13235685-G-A
• rs121908220
• NM_001127222.2:c.4996C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13235685-G-A
• chr19-13235685-G-C
• chr19-13235685-G-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.4996C>T​(p.Arg1666Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,652 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: 0.0000014 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 2.30

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 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 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, 0.961
• PP5: Variant 19-13235685-G-A is Pathogenic according to our data. Variant chr19-13235685-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13235685-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4996C>T	p.Arg1666Trp	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.4996C>T	p.Arg1666Trp	missense_variant	Exon 32 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5014C>T	p.Arg1672Trp	missense_variant	Exon 33 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5002C>T	p.Arg1668Trp	missense_variant	Exon 32 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4999C>T	p.Arg1667Trp	missense_variant	Exon 32 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4999C>T	p.Arg1667Trp	missense_variant	Exon 32 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4999C>T	p.Arg1667Trp	missense_variant	Exon 32 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4858C>T	p.Arg1620Trp	missense_variant	Exon 31 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4999C>T	p.Arg1667Trp	missense_variant	Exon 32 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5014C>T	p.Arg1672Trp	missense_variant	Exon 33 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5005C>T	p.Arg1669Trp	missense_variant	Exon 33 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5002C>T	p.Arg1668Trp	missense_variant	Exon 32 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4999C>T	p.Arg1667Trp	missense_variant	Exon 32 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4999C>T	p.Arg1667Trp	missense_variant	Exon 32 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4999C>T	p.Arg1667Trp	missense_variant	Exon 32 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461652 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727100

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Migraine, familial hemiplegic, 1 Pathogenic:2 Other:1

Apr 25, 2016

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pathogenic variants in CACNA1A have been reported to cause familial hemiplegic migraine. Here we report a case of a female patient with hemiplegic migraine caused by a pathogenic variant in CACNA1A. -

Jun 13, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

Jul 23, 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 tryptophan, which is neutral and slightly polar, at codon 1667 of the CACNA1A protein (p.Arg1667Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hemiplegic migraine (PMID: 11439943). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68433). 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%. This variant disrupts the p.Arg1667 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32170034). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Aug 12, 2019

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found in the total gnomAD dataset, and the data is high quality (0/278210 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Statistically associated with disease, but in a single family (p < 0.05). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;.;D;.;.;.;.;.;D;.;.;D;.;.;.;D;.;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.89	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	0.93	D
MutationAssessor	Pathogenic	5.3	.;.;.;.;H;.;.;.;.;.;.;.;.;.;H;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.96
MutPred		0.81		.;.;Loss of methylation at R1667 (P = 0.0329);Loss of methylation at R1667 (P = 0.0329);Loss of methylation at R1667 (P = 0.0329);.;.;Loss of methylation at R1667 (P = 0.0329);.;.;.;Loss of methylation at R1667 (P = 0.0329);Loss of methylation at R1667 (P = 0.0329);.;Loss of methylation at R1667 (P = 0.0329);.;.;.;.;.;
MVP		0.95
MPC		1.9
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.88
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121908220; hg19: chr19-13346499;