rs1057519429

Variant names:

• chr19-13235666-C-G
• rs1057519429
• NM_001127222.2:c.5015G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-13235666-C-G
• chr19-13235666-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001127222.2(CACNA1A):​c.5015G>C​(p.Arg1672Pro) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1672H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 7.86
• Publications: 7 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr19-13235666-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1305943.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 19-13235666-C-G is Pathogenic according to our data. Variant chr19-13235666-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 375366.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5015G>C	p.Arg1672Pro	missense_variant	Exon 32 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5015G>C	p.Arg1672Pro	missense_variant	Exon 32 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5033G>C	p.Arg1678Pro	missense_variant	Exon 33 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5021G>C	p.Arg1674Pro	missense_variant	Exon 32 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5018G>C	p.Arg1673Pro	missense_variant	Exon 32 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5018G>C	p.Arg1673Pro	missense_variant	Exon 32 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5018G>C	p.Arg1673Pro	missense_variant	Exon 32 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4877G>C	p.Arg1626Pro	missense_variant	Exon 31 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5018G>C	p.Arg1673Pro	missense_variant	Exon 32 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5033G>C	p.Arg1678Pro	missense_variant	Exon 33 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5024G>C	p.Arg1675Pro	missense_variant	Exon 33 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5021G>C	p.Arg1674Pro	missense_variant	Exon 32 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5018G>C	p.Arg1673Pro	missense_variant	Exon 32 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5018G>C	p.Arg1673Pro	missense_variant	Exon 32 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5018G>C	p.Arg1673Pro	missense_variant	Exon 32 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.5018G>C		non_coding_transcript_exon_variant	Exon 32 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*196G>C		non_coding_transcript_exon_variant	Exon 33 of 47			ENSP00000519091.1
CACNA1A	ENST00000713789.1	n.*196G>C		3_prime_UTR_variant	Exon 33 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4479236:Developmental and epileptic encephalopathy, 52 Pathogenic:1

Mar 20, 2022

Wendy Chung Laboratory, Boston Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cerebellar ataxia;C0740279:Cerebellar atrophy;C3714756:Intellectual disability Pathogenic:1

Dec 19, 2015

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely pathogenicity based on finding it once in our study de novo in an 8-year-old female with delayed motor milestones, delayed speech, progressive cerebellar atrophy, hypotonia, and problems with coordination. Our patient has been reported in PMCID:PMC5557584 (patient 1). -

CACNA1A-related disorder Pathogenic:1

Aug 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CACNA1A c.5015G>C variant is predicted to result in the amino acid substitution p.Arg1672Pro. This variant has been confirmed to be de novo in two unrelated individuals with CACNA1A-related disorders (Eldomery et al. 2017. PubMed ID: 28327206; Luo et al. 2017. PubMed ID: 28742085). In vivo modeling of this variant showed alternation in channel activation consistent with a gain-of-function effect (Luo et al. 2017. PubMed ID: 28742085; Tyagi et al. 2019. PubMed ID: 31015257). This variant has not been reported in a large population database, indicating this variant is rare and it is classified as likely pathogenic/pathogenic in ClinVar. Given the evidence, we interpret this variant as likely pathogenic. -

Cerebellar ataxia Pathogenic:1

-

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

This variant was identified, de novo, in an individual with non-fluctuating ataxia. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;.;T;.;.;.;.;.;D;.;.;T;.;.;.;T;.;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.75
MutPred		0.77		.;.;Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);.;.;Loss of MoRF binding (P = 0.0054);.;.;.;Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);.;Loss of MoRF binding (P = 0.0054);.;.;.;.;.;
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.99
Mutation Taster		=19/81	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -5

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

Other links and lift over

dbSNP: rs1057519429; hg19: chr19-13346480;