rs1555773757

Variant names:

• chr19-13359733-C-A
• rs1555773757
• NM_001127222.2:c.851G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001127222.2(CACNA1A):​c.851G>T​(p.Gly284Val) 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.24

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a topological_domain Extracellular (size 86) in uniprot entity CAC1A_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.851G>T	p.Gly284Val	missense_variant	Exon 6 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.851G>T	p.Gly284Val	missense_variant	Exon 6 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.851G>T	p.Gly284Val	missense_variant	Exon 6 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.851G>T	p.Gly284Val	missense_variant	Exon 6 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.851G>T	p.Gly284Val	missense_variant	Exon 6 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.851G>T	p.Gly284Val	missense_variant	Exon 6 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.851G>T	p.Gly284Val	missense_variant	Exon 6 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.710G>T	p.Gly237Val	missense_variant	Exon 5 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.851G>T	p.Gly284Val	missense_variant	Exon 6 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.851G>T	p.Gly284Val	missense_variant	Exon 6 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.851G>T	p.Gly284Val	missense_variant	Exon 6 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.851G>T	p.Gly284Val	missense_variant	Exon 6 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.851G>T	p.Gly284Val	missense_variant	Exon 6 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.851G>T	p.Gly284Val	missense_variant	Exon 6 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.851G>T	p.Gly284Val	missense_variant	Exon 6 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1425388 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 705404

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic ataxia type 2 Uncertain:1

Apr 16, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Inborn genetic diseases Uncertain:1

Sep 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.851G>T (p.G284V) alteration is located in exon 6 (coding exon 6) of the CACNA1A gene. This alteration results from a G to T substitution at nucleotide position 851, causing the glycine (G) at amino acid position 284 to be replaced by a valine (V). for CACNA1A-related neurologic disorders; however, it is unlikely to be causative of CACNA1A-related spinocerebellar ataxia. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy, 42 Uncertain:1

Aug 09, 2021

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes:PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;D;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	.;M;.;.;M;.;.;M;.;.;.;.;M;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.4	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.83
Sift	Benign	0.054	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.068	T;T;.;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen		0.99	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.75
MutPred		0.66		Loss of disorder (P = 0.0311);Loss of disorder (P = 0.0311);Loss of disorder (P = 0.0311);Loss of disorder (P = 0.0311);Loss of disorder (P = 0.0311);.;Loss of disorder (P = 0.0311);Loss of disorder (P = 0.0311);Loss of disorder (P = 0.0311);Loss of disorder (P = 0.0311);Loss of disorder (P = 0.0311);Loss of disorder (P = 0.0311);Loss of disorder (P = 0.0311);Loss of disorder (P = 0.0311);Loss of disorder (P = 0.0311);
MVP		0.95
MPC		2.5
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.61
gMVP		0.98

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: rs1555773757; hg19: chr19-13470547;