NM_001127222.2:c.5263G>A

Variant names:

• chr19-13231847-C-T
• rs121908226
• NM_001127222.2:c.5263G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001127222.2(CACNA1A):​c.5263G>A​(p.Glu1755Lys) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1755G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.78
• Publications: 6 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 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr19-13231846-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3064486.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 19-13231847-C-T is Pathogenic according to our data. Variant chr19-13231847-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8500.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5263G>A	p.Glu1755Lys	missense_variant	Exon 35 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5263G>A	p.Glu1755Lys	missense_variant	Exon 35 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5281G>A	p.Glu1761Lys	missense_variant	Exon 36 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5269G>A	p.Glu1757Lys	missense_variant	Exon 35 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5266G>A	p.Glu1756Lys	missense_variant	Exon 35 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5266G>A	p.Glu1756Lys	missense_variant	Exon 35 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5266G>A	p.Glu1756Lys	missense_variant	Exon 35 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5125G>A	p.Glu1709Lys	missense_variant	Exon 34 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5266G>A	p.Glu1756Lys	missense_variant	Exon 35 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5281G>A	p.Glu1761Lys	missense_variant	Exon 36 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5272G>A	p.Glu1758Lys	missense_variant	Exon 36 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5269G>A	p.Glu1757Lys	missense_variant	Exon 35 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5266G>A	p.Glu1756Lys	missense_variant	Exon 35 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5266G>A	p.Glu1756Lys	missense_variant	Exon 35 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5266G>A	p.Glu1756Lys	missense_variant	Exon 35 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.5266G>A		non_coding_transcript_exon_variant	Exon 35 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*444G>A		non_coding_transcript_exon_variant	Exon 36 of 47			ENSP00000519091.1
CACNA1A	ENST00000713789.1	n.*444G>A		3_prime_UTR_variant	Exon 36 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Episodic ataxia type 2 Pathogenic:1 Other:1

Dec 04, 2007

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;.;T;.;.;.;.;.;D;.;.;T;.;.;.;T;.;.;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.032	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.88
MutPred		0.81		.;.;Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);.;.;Gain of MoRF binding (P = 0.0056);.;.;.;Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);.;Gain of MoRF binding (P = 0.0056);.;.;.;.;.;
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.82
gMVP		0.99
Mutation Taster		=0/100	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: rs121908226; hg19: chr19-13342661;