rs121908219

Variant names:

• chr19-13261552-T-C
• rs121908219
• NM_001127222.2:c.4148A>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001127222.2(CACNA1A):​c.4148A>G​(p.Tyr1383Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.99
• Publications: 14 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 16 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, 9 uncertain in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 19-13261552-T-C is Pathogenic according to our data. Variant chr19-13261552-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8499.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.4148A>G	p.Tyr1383Cys	missense_variant	Exon 26 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4148A>G	p.Tyr1383Cys	missense_variant	Exon 26 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4160A>G	p.Tyr1387Cys	missense_variant	Exon 26 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4154A>G	p.Tyr1385Cys	missense_variant	Exon 26 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4151A>G	p.Tyr1384Cys	missense_variant	Exon 26 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4151A>G	p.Tyr1384Cys	missense_variant	Exon 26 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4151A>G	p.Tyr1384Cys	missense_variant	Exon 26 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4010A>G	p.Tyr1337Cys	missense_variant	Exon 25 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4151A>G	p.Tyr1384Cys	missense_variant	Exon 26 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4160A>G	p.Tyr1387Cys	missense_variant	Exon 26 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4151A>G	p.Tyr1384Cys	missense_variant	Exon 26 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4154A>G	p.Tyr1385Cys	missense_variant	Exon 26 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4151A>G	p.Tyr1384Cys	missense_variant	Exon 26 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4151A>G	p.Tyr1384Cys	missense_variant	Exon 26 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4151A>G	p.Tyr1384Cys	missense_variant	Exon 26 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.4151A>G		non_coding_transcript_exon_variant	Exon 26 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.4148A>G		non_coding_transcript_exon_variant	Exon 26 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Oct 10, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jan 13, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect through loss of function in Cav2.1 channel activity (PMID: 33557884); 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: 8898206, 9915947, 28058944, 36305856, 37422902, 20837964, 11061267, 22082423, 28717674, 35936582, 33557884) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.48	.;.;.;.;N;.;.;.;.;.;.;.;N;.;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-8.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.72
MutPred		0.76		.;.;Gain of catalytic residue at I1382 (P = 0.1729);Gain of catalytic residue at I1382 (P = 0.1729);Gain of catalytic residue at I1382 (P = 0.1729);.;Gain of catalytic residue at I1382 (P = 0.1729);.;.;Gain of catalytic residue at I1382 (P = 0.1729);Gain of catalytic residue at I1382 (P = 0.1729);.;Gain of catalytic residue at I1382 (P = 0.1729);.;Gain of catalytic residue at I1382 (P = 0.1729);
MVP		0.98
MPC		2.7
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.80
gMVP		0.99
Mutation Taster		=4/96	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: rs121908219; hg19: chr19-13372366;