chr19-13298821-C-G

Position:

• chr19-13298821-C-G

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.2812G>C​(p.Gly938Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,573,176 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 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.01

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 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=0.2503152).
• BP6: Variant 19-13298821-C-G is Benign according to our data. Variant chr19-13298821-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 422044.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2812G>C	p.Gly938Arg	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.2812G>C	p.Gly938Arg	missense_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2824G>C	p.Gly942Arg	missense_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2818G>C	p.Gly940Arg	missense_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2815G>C	p.Gly939Arg	missense_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2815G>C	p.Gly939Arg	missense_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2815G>C	p.Gly939Arg	missense_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2674G>C	p.Gly892Arg	missense_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2815G>C	p.Gly939Arg	missense_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2824G>C	p.Gly942Arg	missense_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2815G>C	p.Gly939Arg	missense_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2818G>C	p.Gly940Arg	missense_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2815G>C	p.Gly939Arg	missense_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2815G>C	p.Gly939Arg	missense_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2815G>C	p.Gly939Arg	missense_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152184 Hom.: 0 Cov.: 33

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000366 AC: 7 AN: 191208 Hom.: 0 AF XY: 0.0000466 AC XY: 5 AN XY: 107190

Gnomad AFR exome AF: 0.00

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: 0.0000806

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000172 AC: 244 AN: 1420992 Hom.: 0 Cov.: 32 AF XY: 0.000177 AC XY: 125 AN XY: 705812

Gnomad4 AFR exome AF: 0.0000322

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: 0.000219

Gnomad4 OTH exome AF: 0.0000339

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74346

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: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000352 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31719132) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 27, 2023	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 seen where an alternate explanation for disease was also identified, suggesting this variant may not cause disease. Computational tools predict that this variant is not damaging. -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	14
DANN	Benign	0.51
DEOGEN2	Benign	0.35	.;T;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.065	D
MutationAssessor	Benign	1.1	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.8	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.54
Sift	Benign	0.072	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.086	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.070
MutPred		0.23		.;.;Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);.;Gain of solvent accessibility (P = 0.0037);.;.;Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);.;Gain of solvent accessibility (P = 0.0037);.;Gain of solvent accessibility (P = 0.0037);
MVP		0.95
MPC		2.1
ClinPred		0.11	T
GERP RS		1.3
Varity_R		0.10
gMVP		0.44

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: rs771423362; hg19: chr19-13409635;