rs1057521920

Variant names:

• chr19-13452889-C-G
• rs1057521920
• NM_001127222.2:c.526G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-13452889-C-G
• chr19-13452889-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001127222.2(CACNA1A):​c.526G>C​(p.Val176Leu) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V176M) has been classified as Likely pathogenic.

• 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: 7.76
• Publications: 1 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain 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 chr19-13452889-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 426878.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.526G>C	p.Val176Leu	missense_variant	Exon 3 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2	c.526G>C	p.Val176Leu	missense_variant	Exon 3 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.526G>C	p.Val176Leu	missense_variant	Exon 3 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2	c.526G>C	p.Val176Leu	missense_variant	Exon 3 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1	c.526G>C	p.Val176Leu	missense_variant	Exon 3 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.526G>C	p.Val176Leu	missense_variant	Exon 3 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.526G>C	p.Val176Leu	missense_variant	Exon 3 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.526G>C	p.Val176Leu	missense_variant	Exon 3 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.526G>C	p.Val176Leu	missense_variant	Exon 3 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.385G>C	p.Val129Leu	missense_variant	Exon 2 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.526G>C	p.Val176Leu	missense_variant	Exon 3 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.526G>C	p.Val176Leu	missense_variant	Exon 3 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.526G>C	p.Val176Leu	missense_variant	Exon 3 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.526G>C	p.Val176Leu	missense_variant	Exon 3 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.526G>C	p.Val176Leu	missense_variant	Exon 3 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1	c.526G>C	p.Val176Leu	missense_variant	Exon 3 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.526G>C		non_coding_transcript_exon_variant	Exon 3 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.526G>C		non_coding_transcript_exon_variant	Exon 3 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jul 06, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CACNA1A-related disease. ClinVar contains an entry for this variant (Variation ID: 384320). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 176 of the CACNA1A protein (p.Val176Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. -

not provided Uncertain:1

Feb 29, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the CACNA1A gene. The V176L variant hasnot been published as a pathogenic variant, nor has it been reported as a benign variant to ourknowledge. It was not observed in approximately 6,200 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant inthese populations. The V176L variant is a conservative amino acid substitution, which is not likely toimpact secondary protein structure as these residues share similar properties. However, thissubstitution occurs at a position that is conserved across species and in silico analysis predicts thisvariant is probably damaging to the protein structure/function. Therefore, based on the currentlyavailable information, it is unclear whether this variant is a pathogenic variant or a rare benignvariant. -

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	0.90	.;D;T;.;.;.;.;.;.;T;.;.;.;T;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	.;M;.;.;M;.;.;M;.;.;.;.;M;.;.;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.3	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.015	D;D;.;.;.;.;.;.;.;.;.;D;.;.;.;D
Polyphen		1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.74
MutPred		0.64		Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);.;Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);.;
MVP		0.97
MPC		1.3
ClinPred		0.93	D
GERP RS		5.8
Varity_R		0.75
gMVP		0.95
Mutation Taster		=7/93	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: rs1057521920; hg19: chr19-13563703;