rs200093958

Variant names:

• chr19-13212141-G-A
• rs200093958
• NM_001127222.2:c.6265C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13212141-G-A
• chr19-13212141-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2 PP3 BP6 BS2

The NM_001127222.2(CACNA1A):​c.6265C>T​(p.Arg2089Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R2089R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.891

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 -3 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747
• BP6: Variant 19-13212141-G-A is Benign according to our data. Variant chr19-13212141-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1752525.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6265C>T	p.Arg2089Trp	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.6265C>T	p.Arg2089Trp	missense_variant	Exon 43 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6283C>T	p.Arg2095Trp	missense_variant	Exon 44 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6271C>T	p.Arg2091Trp	missense_variant	Exon 43 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6268C>T	p.Arg2090Trp	missense_variant	Exon 43 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6268C>T	p.Arg2090Trp	missense_variant	Exon 43 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6268C>T	p.Arg2090Trp	missense_variant	Exon 43 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6127C>T	p.Arg2043Trp	missense_variant	Exon 42 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6268C>T	p.Arg2090Trp	missense_variant	Exon 43 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6283C>T	p.Arg2095Trp	missense_variant	Exon 44 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6274C>T	p.Arg2092Trp	missense_variant	Exon 44 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6271C>T	p.Arg2091Trp	missense_variant	Exon 43 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6268C>T	p.Arg2090Trp	missense_variant	Exon 43 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6268C>T	p.Arg2090Trp	missense_variant	Exon 43 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6268C>T	p.Arg2090Trp	missense_variant	Exon 43 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*567C>T		non_coding_transcript_exon_variant	Exon 8 of 10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*567C>T		3_prime_UTR_variant	Exon 8 of 10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 34

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248168 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134852

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461292 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 726980

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74368

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: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 24, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R2090W variant (also known as c.6268C>T), located in coding exon 43 of the CACNA1A gene, results from a C to T substitution at nucleotide position 6268. The arginine at codon 2090 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1A: PP2 -

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

Oct 16, 2024

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	Uncertain	0.53
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.70	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.058	D
MutationAssessor	Pathogenic	3.1	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.4	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0080	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.89
MutPred		0.35		.;.;Loss of methylation at R2090 (P = 0.0195);Loss of methylation at R2090 (P = 0.0195);Loss of methylation at R2090 (P = 0.0195);.;.;Loss of methylation at R2090 (P = 0.0195);.;.;.;Loss of methylation at R2090 (P = 0.0195);Loss of methylation at R2090 (P = 0.0195);.;Loss of methylation at R2090 (P = 0.0195);.;.;.;
MVP		0.83
MPC		0.83
ClinPred		0.99	D
GERP RS		-1.5
Varity_R		0.49
gMVP		0.71

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: rs200093958; hg19: chr19-13322955;