19-13212506-C-G

Variant names:

• chr19-13212506-C-G
• rs574805525
• NM_001127222.2:c.6067G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001127222.2(CACNA1A):​c.6067G>C​(p.Gly2023Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,423,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. G2023S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.821
• 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

ENSG00000300728 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33259445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6067G>C	p.Gly2023Arg	missense_variant	Exon 42 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6067G>C	p.Gly2023Arg	missense_variant	Exon 42 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6085G>C	p.Gly2029Arg	missense_variant	Exon 43 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6073G>C	p.Gly2025Arg	missense_variant	Exon 42 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6070G>C	p.Gly2024Arg	missense_variant	Exon 42 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6070G>C	p.Gly2024Arg	missense_variant	Exon 42 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6070G>C	p.Gly2024Arg	missense_variant	Exon 42 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5929G>C	p.Gly1977Arg	missense_variant	Exon 41 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6070G>C	p.Gly2024Arg	missense_variant	Exon 42 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6085G>C	p.Gly2029Arg	missense_variant	Exon 43 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6076G>C	p.Gly2026Arg	missense_variant	Exon 43 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6073G>C	p.Gly2025Arg	missense_variant	Exon 42 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6070G>C	p.Gly2024Arg	missense_variant	Exon 42 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6070G>C	p.Gly2024Arg	missense_variant	Exon 42 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6070G>C	p.Gly2024Arg	missense_variant	Exon 42 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.*369G>C		non_coding_transcript_exon_variant	Exon 41 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*1282G>C		non_coding_transcript_exon_variant	Exon 43 of 47			ENSP00000519091.1
CACNA1A	ENST00000636768.2	n.*369G>C		3_prime_UTR_variant	Exon 41 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*1282G>C		3_prime_UTR_variant	Exon 43 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1423994 Hom.: 0 Cov.: 34 AF XY: 0.00000142 AC XY: 1 AN XY: 704852

African (AFR) AF: 0.00 AC: 0 AN: 32684

American (AMR) AF: 0.00 AC: 0 AN: 37892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25336

East Asian (EAS) AF: 0.00 AC: 0 AN: 37834

South Asian (SAS) AF: 0.00 AC: 0 AN: 81800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1092764

Other (OTH) AF: 0.00 AC: 0 AN: 59040

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 26, 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 glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2024 of the CACNA1A protein (p.Gly2024Arg). This variant is not present in population databases (gnomAD no frequency). 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 not expected to disrupt CACNA1A protein function. 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	Benign	0.20
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	15
DANN	Benign	0.84
DEOGEN2	Benign	0.060	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.2	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.
PhyloP100		0.82
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.8	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.28
Sift	Benign	0.042	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.082	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.34
MutPred		0.30		.;.;Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);.;.;Gain of MoRF binding (P = 0.0213);.;.;.;Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);.;Gain of MoRF binding (P = 0.0213);.;.;.;
MVP		0.90
MPC		1.0
ClinPred		0.96	D
GERP RS		1.9
Varity_R		0.27
gMVP		0.64
Mutation Taster		=69/31	polymorphism

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: rs574805525; hg19: chr19-13323320;