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. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1666Q) has been classified 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
• 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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr19-13235684-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 585575.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 68433.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.4996C>T	p.Arg1666Trp	missense_variant	Exon 32 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2	c.4999C>T	p.Arg1667Trp	missense_variant	Exon 32 of 47	ENST00000638009.2	NP_001120693.1

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	ENST00000638009.2	c.4999C>T	p.Arg1667Trp	missense_variant	Exon 32 of 47	1	NM_001127221.2	ENSP00000489913.1
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	ENST00000637276.1	c.4999C>T	p.Arg1667Trp	missense_variant	Exon 32 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.4999C>T		non_coding_transcript_exon_variant	Exon 32 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*177C>T		non_coding_transcript_exon_variant	Exon 33 of 47			ENSP00000519091.1
CACNA1A	ENST00000713789.1	n.*177C>T		3_prime_UTR_variant	Exon 33 of 47			ENSP00000519091.1

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

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111836

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

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

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

- -

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. -

-

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;.;.;.;.;.
PhyloP100		2.3
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
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908220; hg19: chr19-13346499;