19-13298580-C-T

Position:

• chr19-13298580-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001127222.2(CACNA1A):​c.3053G>A​(p.Arg1018Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,390,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

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 -5 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.2296961).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3053G>A	p.Arg1018Gln	missense_variant	19/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3053G>A	p.Arg1018Gln	missense_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3065G>A	p.Arg1022Gln	missense_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3059G>A	p.Arg1020Gln	missense_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3056G>A	p.Arg1019Gln	missense_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3056G>A	p.Arg1019Gln	missense_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3056G>A	p.Arg1019Gln	missense_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2915G>A	p.Arg972Gln	missense_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3056G>A	p.Arg1019Gln	missense_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3065G>A	p.Arg1022Gln	missense_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3056G>A	p.Arg1019Gln	missense_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3059G>A	p.Arg1020Gln	missense_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3056G>A	p.Arg1019Gln	missense_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3056G>A	p.Arg1019Gln	missense_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3056G>A	p.Arg1019Gln	missense_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152168 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000108 AC: 15 AN: 1390726 Hom.: 0 Cov.: 32 AF XY: 0.0000117 AC XY: 8 AN XY: 685890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000140

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74350

Gnomad4 AFR AF: 0.00

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 04, 2018

This variant has not been reported in the literature in individuals with CACNA1A-related disease. 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 1019 of the CACNA1A protein (p.Arg1019Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.016	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.053	N
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.3	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.83	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.28
Sift	Benign	0.36	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.37	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.18
MutPred		0.35		.;.;Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);.;Gain of helix (P = 0.0199);.;.;Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);.;Gain of helix (P = 0.0199);.;Gain of helix (P = 0.0199);
MVP		0.81
MPC		2.2
ClinPred		0.55	D
GERP RS		2.5
Varity_R		0.074
gMVP		0.25

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: rs762288499; hg19: chr19-13409394;