chr19-13212637-C-T

Variant names:

• chr19-13212637-C-T
• rs772988279
• NM_001127222.2:c.6044G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_001127222.2(CACNA1A):​c.6044G>A​(p.Gly2015Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000948 in 1,518,780 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.13

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 Likely_benign. Variant got -6 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20461023).
• BP6: Variant 19-13212637-C-T is Benign according to our data. Variant chr19-13212637-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 585578.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6044G>A	p.Gly2015Glu	missense_variant	Exon 41 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6044G>A	p.Gly2015Glu	missense_variant	Exon 41 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6062G>A	p.Gly2021Glu	missense_variant	Exon 42 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6050G>A	p.Gly2017Glu	missense_variant	Exon 41 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6047G>A	p.Gly2016Glu	missense_variant	Exon 41 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6047G>A	p.Gly2016Glu	missense_variant	Exon 41 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6047G>A	p.Gly2016Glu	missense_variant	Exon 41 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5906G>A	p.Gly1969Glu	missense_variant	Exon 40 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6047G>A	p.Gly2016Glu	missense_variant	Exon 41 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6062G>A	p.Gly2021Glu	missense_variant	Exon 42 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6053G>A	p.Gly2018Glu	missense_variant	Exon 42 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6050G>A	p.Gly2017Glu	missense_variant	Exon 41 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6047G>A	p.Gly2016Glu	missense_variant	Exon 41 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6047G>A	p.Gly2016Glu	missense_variant	Exon 41 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6047G>A	p.Gly2016Glu	missense_variant	Exon 41 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*346G>A		non_coding_transcript_exon_variant	Exon 6 of 10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*346G>A		3_prime_UTR_variant	Exon 6 of 10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000386 AC: 6 AN: 155516 Hom.: 0 AF XY: 0.0000367 AC XY: 3 AN XY: 81676

Gnomad AFR exome AF: 0.0000922

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000715

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000980 AC: 134 AN: 1366672 Hom.: 0 Cov.: 33 AF XY: 0.000105 AC XY: 70 AN XY: 668572

Gnomad4 AFR exome AF: 0.0000643

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000559

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74308

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.0000419 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Oct 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2016 of the CACNA1A protein (p.Gly2016Glu). This variant is present in population databases (rs772988279, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of CACNA1A-related conditions (PMID: 33879512; Invitae). ClinVar contains an entry for this variant (Variation ID: 585578). 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 with a negative predictive value of 95%. 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. -

not provided Uncertain:1

Jul 30, 2024

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with this gene. Polyphen and MutationTaster predict this amino acid change may be benign. -

Inborn genetic diseases Benign:1

Jul 19, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.00092	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.76	.;D;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.0063	T
MutationAssessor	Uncertain	2.1	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.4	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.078	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.16	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.16
MVP		0.85
MPC		1.1
ClinPred		0.15	T
GERP RS		2.2
Varity_R		0.25
gMVP		0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs772988279; hg19: chr19-13323451; COSMIC: COSV100800516; COSMIC: COSV100800516;