19-13212203-C-T

Variant names:

• chr19-13212203-C-T
• rs769040794
• NM_001127222.2:c.6203G>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.6203G>A​(p.Arg2068Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.83

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=0.18344748).
• BP6: Variant 19-13212203-C-T is Benign according to our data. Variant chr19-13212203-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 426943.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6203G>A	p.Arg2068Gln	missense_variant	Exon 43 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6203G>A	p.Arg2068Gln	missense_variant	Exon 43 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6221G>A	p.Arg2074Gln	missense_variant	Exon 44 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6209G>A	p.Arg2070Gln	missense_variant	Exon 43 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6206G>A	p.Arg2069Gln	missense_variant	Exon 43 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6206G>A	p.Arg2069Gln	missense_variant	Exon 43 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6206G>A	p.Arg2069Gln	missense_variant	Exon 43 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6065G>A	p.Arg2022Gln	missense_variant	Exon 42 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6206G>A	p.Arg2069Gln	missense_variant	Exon 43 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6221G>A	p.Arg2074Gln	missense_variant	Exon 44 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6212G>A	p.Arg2071Gln	missense_variant	Exon 44 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6209G>A	p.Arg2070Gln	missense_variant	Exon 43 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6206G>A	p.Arg2069Gln	missense_variant	Exon 43 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6206G>A	p.Arg2069Gln	missense_variant	Exon 43 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6206G>A	p.Arg2069Gln	missense_variant	Exon 43 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*505G>A		non_coding_transcript_exon_variant	Exon 8 of 10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*505G>A		3_prime_UTR_variant	Exon 8 of 10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152220 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248676 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135056

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: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461494 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 727066

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152220 Hom.: 0 Cov.: 34 AF XY: 0.0000538 AC XY: 4 AN XY: 74362

Gnomad4 AFR AF: 0.0000724

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Jun 22, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Feb 10, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Mar 07, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.023	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.2	.;.;.;.;L;.;.;.;.;.;.;.;.;.;L;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.50	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.69	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.34
MutPred		0.19		.;.;Gain of phosphorylation at S2065 (P = 0.1631);Gain of phosphorylation at S2065 (P = 0.1631);Gain of phosphorylation at S2065 (P = 0.1631);.;.;Gain of phosphorylation at S2065 (P = 0.1631);.;.;.;Gain of phosphorylation at S2065 (P = 0.1631);Gain of phosphorylation at S2065 (P = 0.1631);.;Gain of phosphorylation at S2065 (P = 0.1631);.;.;.;
MVP		0.78
MPC		0.55
ClinPred		0.47	T
GERP RS		3.4
Varity_R		0.070
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: rs769040794; hg19: chr19-13323017;