rs794727411

Variant names:

• chr19-13261526-C-A
• NM_001127222.2:c.4174G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13261526-C-A
• chr19-13261526-C-G
• chr19-13261526-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_001127222.2(CACNA1A):​c.4174G>T​(p.Val1392Leu) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1392M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.88

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 repeat III (size 283) in uniprot entity CAC1A_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) 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 chr19-13261526-C-T is described in Lovd as [Likely_pathogenic].
• 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, 0.875
• PP5: Variant 19-13261526-C-A is Pathogenic according to our data. Variant chr19-13261526-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1285568.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4174G>T	p.Val1392Leu	missense_variant	Exon 26 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4174G>T	p.Val1392Leu	missense_variant	Exon 26 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4186G>T	p.Val1396Leu	missense_variant	Exon 26 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4180G>T	p.Val1394Leu	missense_variant	Exon 26 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4177G>T	p.Val1393Leu	missense_variant	Exon 26 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4177G>T	p.Val1393Leu	missense_variant	Exon 26 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4177G>T	p.Val1393Leu	missense_variant	Exon 26 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4036G>T	p.Val1346Leu	missense_variant	Exon 25 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4177G>T	p.Val1393Leu	missense_variant	Exon 26 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4186G>T	p.Val1396Leu	missense_variant	Exon 26 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4177G>T	p.Val1393Leu	missense_variant	Exon 26 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4180G>T	p.Val1394Leu	missense_variant	Exon 26 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4177G>T	p.Val1393Leu	missense_variant	Exon 26 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4177G>T	p.Val1393Leu	missense_variant	Exon 26 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4177G>T	p.Val1393Leu	missense_variant	Exon 26 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: 1448688 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719322

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 42 Pathogenic:1

Sep 09, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed). -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1

Nov 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1393 of the CACNA1A protein (p.Val1393Leu). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 1285568). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1A protein function. This variant disrupts the p.Val1393 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28007337, 29056246, 29100083, 30283815, 31468518). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.051	T;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.79
MutPred		0.70		.;.;Loss of catalytic residue at V1393 (P = 0.038);Loss of catalytic residue at V1393 (P = 0.038);Loss of catalytic residue at V1393 (P = 0.038);.;Loss of catalytic residue at V1393 (P = 0.038);.;.;Loss of catalytic residue at V1393 (P = 0.038);Loss of catalytic residue at V1393 (P = 0.038);.;Loss of catalytic residue at V1393 (P = 0.038);.;Loss of catalytic residue at V1393 (P = 0.038);
MVP		0.94
MPC		2.2
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.41
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-13372340;