19-13259589-C-G

Variant names:

• chr19-13259589-C-G
• rs121908237
• NM_001127222.2:c.4363G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001127222.2(CACNA1A):​c.4363G>C​(p.Val1455Leu) 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1455M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 29)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91
• Publications: 3 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 12 ACMG points.

• PS1: Transcript NM_001127222.2 (CACNA1A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-13259589-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 946947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant 19-13259589-C-G is Pathogenic according to our data. Variant chr19-13259589-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1740050.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4363G>C	p.Val1455Leu	missense_variant	Exon 27 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4363G>C	p.Val1455Leu	missense_variant	Exon 27 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4375G>C	p.Val1459Leu	missense_variant	Exon 27 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4369G>C	p.Val1457Leu	missense_variant	Exon 27 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4366G>C	p.Val1456Leu	missense_variant	Exon 27 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4366G>C	p.Val1456Leu	missense_variant	Exon 27 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4366G>C	p.Val1456Leu	missense_variant	Exon 27 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4225G>C	p.Val1409Leu	missense_variant	Exon 26 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4366G>C	p.Val1456Leu	missense_variant	Exon 27 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4375G>C	p.Val1459Leu	missense_variant	Exon 27 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4366G>C	p.Val1456Leu	missense_variant	Exon 27 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4369G>C	p.Val1457Leu	missense_variant	Exon 27 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4366G>C	p.Val1456Leu	missense_variant	Exon 27 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4366G>C	p.Val1456Leu	missense_variant	Exon 27 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4366G>C	p.Val1456Leu	missense_variant	Exon 27 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.4366G>C		non_coding_transcript_exon_variant	Exon 27 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.4363G>C		non_coding_transcript_exon_variant	Exon 27 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Sep 04, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V1456L variant (also known as c.4366G>C), located in coding exon 27 of the CACNA1A gene, results from a G to C substitution at nucleotide position 4366. The valine at codon 1456 is replaced by leucine, an amino acid with highly similar properties. This variant (reported as V1457L) was detected in 8 affected individuals form one familial hemiplegic migraine family and was absent in 4 unaffected family members (Carrera P et al. Neurology, 1999 Jul;53:26-33). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	.;.;.;.;M;.;.;.;.;.;.;.;M;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0050	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.91
MutPred		0.74		.;.;Loss of catalytic residue at V1456 (P = 0.0762);Loss of catalytic residue at V1456 (P = 0.0762);Loss of catalytic residue at V1456 (P = 0.0762);.;Loss of catalytic residue at V1456 (P = 0.0762);.;.;Loss of catalytic residue at V1456 (P = 0.0762);Loss of catalytic residue at V1456 (P = 0.0762);.;Loss of catalytic residue at V1456 (P = 0.0762);.;Loss of catalytic residue at V1456 (P = 0.0762);.;
MVP		0.99
MPC		2.2
ClinPred		0.99	D
GERP RS		4.9
PromoterAI		-0.0056	Neutral
Varity_R		0.50
gMVP		0.97
Mutation Taster		=3/97	disease causing

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: rs121908237; hg19: chr19-13370403;