rs1555767914

Variant names:

• chr19-13335828-G-A
• rs1555767914
• NM_001127222.2:c.1060C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13335828-G-A
• chr19-13335828-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001127222.2(CACNA1A):​c.1060C>T​(p.Leu354Phe) variant causes a missense change involving the alteration of a non-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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L354H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 3.18

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 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain 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, 0.939
• PP5: Variant 19-13335828-G-A is Pathogenic according to our data. Variant chr19-13335828-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437417.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.1060C>T	p.Leu354Phe	missense_variant	Exon 7 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1060C>T	p.Leu354Phe	missense_variant	Exon 7 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1060C>T	p.Leu354Phe	missense_variant	Exon 7 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1060C>T	p.Leu354Phe	missense_variant	Exon 7 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1060C>T	p.Leu354Phe	missense_variant	Exon 7 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1060C>T	p.Leu354Phe	missense_variant	Exon 7 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1060C>T	p.Leu354Phe	missense_variant	Exon 7 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.919C>T	p.Leu307Phe	missense_variant	Exon 6 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1060C>T	p.Leu354Phe	missense_variant	Exon 7 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1060C>T	p.Leu354Phe	missense_variant	Exon 7 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1060C>T	p.Leu354Phe	missense_variant	Exon 7 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1060C>T	p.Leu354Phe	missense_variant	Exon 7 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1060C>T	p.Leu354Phe	missense_variant	Exon 7 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1060C>T	p.Leu354Phe	missense_variant	Exon 7 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1060C>T	p.Leu354Phe	missense_variant	Exon 7 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Jun 14, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Migraine, familial hemiplegic, 1 Pathogenic:1

Feb 08, 2017

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Jan 02, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CACNA1A c.1060C>T (p.Leu354Phe) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 242656 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1060C>T in individuals affected with Epileptic Encephalopathy, Early Infantile, 42 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 437417). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	.;H;.;.;H;.;.;H;.;.;.;.;H;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.4	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;.;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.76
MutPred		0.79		Loss of stability (P = 0.5312);Loss of stability (P = 0.5312);Loss of stability (P = 0.5312);Loss of stability (P = 0.5312);Loss of stability (P = 0.5312);.;Loss of stability (P = 0.5312);Loss of stability (P = 0.5312);Loss of stability (P = 0.5312);Loss of stability (P = 0.5312);Loss of stability (P = 0.5312);Loss of stability (P = 0.5312);Loss of stability (P = 0.5312);Loss of stability (P = 0.5312);Loss of stability (P = 0.5312);
MVP		0.96
MPC		2.3
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.82
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555767914; hg19: chr19-13446642;