rs1555732391

Variant names:

• chr19-13214282-T-C
• rs1555732391
• NM_001127222.2:c.5891A>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001127222.2(CACNA1A):​c.5891A>G​(p.Tyr1964Cys) 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.68

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 Uncertain_significance. Variant got 5 ACMG points.

• 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, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5891A>G	p.Tyr1964Cys	missense_variant	Exon 40 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5891A>G	p.Tyr1964Cys	missense_variant	Exon 40 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5909A>G	p.Tyr1970Cys	missense_variant	Exon 41 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5897A>G	p.Tyr1966Cys	missense_variant	Exon 40 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5894A>G	p.Tyr1965Cys	missense_variant	Exon 40 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5894A>G	p.Tyr1965Cys	missense_variant	Exon 40 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5894A>G	p.Tyr1965Cys	missense_variant	Exon 40 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5753A>G	p.Tyr1918Cys	missense_variant	Exon 39 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5894A>G	p.Tyr1965Cys	missense_variant	Exon 40 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5909A>G	p.Tyr1970Cys	missense_variant	Exon 41 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5900A>G	p.Tyr1967Cys	missense_variant	Exon 41 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5897A>G	p.Tyr1966Cys	missense_variant	Exon 40 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5894A>G	p.Tyr1965Cys	missense_variant	Exon 40 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5894A>G	p.Tyr1965Cys	missense_variant	Exon 40 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5894A>G	p.Tyr1965Cys	missense_variant	Exon 40 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*193A>G		non_coding_transcript_exon_variant	Exon 5 of 10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*193A>G		3_prime_UTR_variant	Exon 5 of 10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5894A>G (p.Y1965C) alteration is located in coding exon 40 of the CACNA1A gene. This alteration results from an A to G substitution at nucleotide position 5894, causing the tyrosine (Y) at amino acid position 1965 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Jun 27, 2023

GeneDx

Significance: Uncertain significance

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.6	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.1	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.016	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.035	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.86
MutPred		0.73		.;.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);.;.;Loss of helix (P = 0.0558);.;.;.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);.;Loss of helix (P = 0.0558);.;.;.;.;
MVP		0.84
MPC		0.96
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.83
gMVP		0.92

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: rs1555732391; hg19: chr19-13325096;