rs1555774867

Variant names:

• chr19-13365458-C-T
• rs1555774867
• NM_001127222.2:c.643G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_001127222.2(CACNA1A):​c.643G>A​(p.Val215Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,370 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V215A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.81
• Publications: 0 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 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr19-13365457-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 803536.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.643G>A	p.Val215Ile	missense_variant	Exon 5 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.643G>A	p.Val215Ile	missense_variant	Exon 5 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.643G>A	p.Val215Ile	missense_variant	Exon 5 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.643G>A	p.Val215Ile	missense_variant	Exon 5 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.643G>A	p.Val215Ile	missense_variant	Exon 5 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.643G>A	p.Val215Ile	missense_variant	Exon 5 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.643G>A	p.Val215Ile	missense_variant	Exon 5 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.502G>A	p.Val168Ile	missense_variant	Exon 4 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.643G>A	p.Val215Ile	missense_variant	Exon 5 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.643G>A	p.Val215Ile	missense_variant	Exon 5 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.643G>A	p.Val215Ile	missense_variant	Exon 5 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.643G>A	p.Val215Ile	missense_variant	Exon 5 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.643G>A	p.Val215Ile	missense_variant	Exon 5 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.643G>A	p.Val215Ile	missense_variant	Exon 5 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.643G>A	p.Val215Ile	missense_variant	Exon 5 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.643G>A		non_coding_transcript_exon_variant	Exon 5 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.643G>A		non_coding_transcript_exon_variant	Exon 5 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461370 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726968

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111668

Other (OTH) AF: 0.00 AC: 0 AN: 60356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Feb 21, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 08, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine with isoleucine at codon 215 of the CACNA1A protein (p.Val215Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CACNA1A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;D;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.4	.;M;.;.;M;.;.;M;.;.;.;.;M;.;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.84	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0070	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.014	D;D;.;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen		0.95	.;P;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.37
MutPred		0.60		Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);.;Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);
MVP		0.89
MPC		1.6
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.54
gMVP		0.86
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs1555774867; hg19: chr19-13476272;