rs190551509

Positions:

• chr19-13298590-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001127222.2(CACNA1A):​c.3043G>A​(p.Gly1015Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000402 in 1,541,918 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (1 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: -0.551

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 Benign. Variant got -12 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=0.03501746).
• BP6: Variant 19-13298590-C-T is Benign according to our data. Variant chr19-13298590-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 391779.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000302 (42/1389662) while in subpopulation AFR AF= 0.000937 (28/29892). AF 95% confidence interval is 0.000665. There are 1 homozygotes in gnomad4_exome. There are 17 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3043G>A	p.Gly1015Arg	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.3043G>A	p.Gly1015Arg	missense_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3055G>A	p.Gly1019Arg	missense_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3049G>A	p.Gly1017Arg	missense_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3046G>A	p.Gly1016Arg	missense_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3046G>A	p.Gly1016Arg	missense_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3046G>A	p.Gly1016Arg	missense_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2905G>A	p.Gly969Arg	missense_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3046G>A	p.Gly1016Arg	missense_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3055G>A	p.Gly1019Arg	missense_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3046G>A	p.Gly1016Arg	missense_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3049G>A	p.Gly1017Arg	missense_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3046G>A	p.Gly1016Arg	missense_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3046G>A	p.Gly1016Arg	missense_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3046G>A	p.Gly1016Arg	missense_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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

GnomAD3 exomes AF: 0.0000138 AC: 2 AN: 144838 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 77216

Gnomad AFR exome AF: 0.000332

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000302 AC: 42 AN: 1389662 Hom.: 1 Cov.: 32 AF XY: 0.0000248 AC XY: 17 AN XY: 685376

Gnomad4 AFR exome AF: 0.000937

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000254

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.31e-7

Gnomad4 OTH exome AF: 0.000139

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74460

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000131

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

Alfa AF: 0.0000277 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000320 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 11, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 22, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2019	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2023

The c.3046G>A (p.G1016R) alteration is located in exon 19 (coding exon 19) of the CACNA1A gene. This alteration results from a G to A substitution at nucleotide position 3046, causing the glycine (G) at amino acid position 1016 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.95
DANN	Benign	0.84
DEOGEN2	Benign	0.031	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.85	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.035	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.1	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.7	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.49	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.16	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.080
MutPred		0.19		.;.;Gain of MoRF binding (P = 0.0682);Gain of MoRF binding (P = 0.0682);Gain of MoRF binding (P = 0.0682);.;Gain of MoRF binding (P = 0.0682);.;.;Gain of MoRF binding (P = 0.0682);Gain of MoRF binding (P = 0.0682);.;Gain of MoRF binding (P = 0.0682);.;Gain of MoRF binding (P = 0.0682);
MVP		0.76
MPC		1.3
ClinPred		0.020	T
GERP RS		-1.7
Varity_R		0.14
gMVP		0.24

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: rs190551509; hg19: chr19-13409404;