NM_001127222.2:c.6715C>T

Variant names:

• chr19-13208821-G-A
• rs759576380
• NM_001127222.2:c.6715C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_001127222.2(CACNA1A):​c.6715C>T​(p.Arg2239Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,544,102 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.300

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.
• 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.6715C>T	p.Arg2239Trp	missense_variant	Exon 46 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6715C>T	p.Arg2239Trp	missense_variant	Exon 46 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6733C>T	p.Arg2245Trp	missense_variant	Exon 47 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6721C>T	p.Arg2241Trp	missense_variant	Exon 46 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6718C>T	p.Arg2240Trp	missense_variant	Exon 46 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6718C>T	p.Arg2240Trp	missense_variant	Exon 46 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6682C>T	p.Arg2228Trp	missense_variant	Exon 45 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6577C>T	p.Arg2193Trp	missense_variant	Exon 45 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6718C>T	p.Arg2240Trp	missense_variant	Exon 46 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6733C>T	p.Arg2245Trp	missense_variant	Exon 47 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6724C>T	p.Arg2242Trp	missense_variant	Exon 47 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6721C>T	p.Arg2241Trp	missense_variant	Exon 46 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6718C>T	p.Arg2240Trp	missense_variant	Exon 46 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6718C>T	p.Arg2240Trp	missense_variant	Exon 46 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6682C>T	p.Arg2228Trp	missense_variant	Exon 45 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*981C>T		downstream_gene_variant		5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151912 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000542 AC: 8 AN: 147666 Hom.: 0 AF XY: 0.0000492 AC XY: 4 AN XY: 81340

Gnomad AFR exome AF: 0.000131

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: 0.000116

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000130 AC: 181 AN: 1392190 Hom.: 0 Cov.: 36 AF XY: 0.000134 AC XY: 92 AN XY: 688096

Gnomad4 AFR exome AF: 0.0000624

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000274

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000161

Gnomad4 OTH exome AF: 0.0000517

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151912 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74178

Gnomad4 AFR AF: 0.0000242

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: 0.0000589

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.0000733 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Jun 04, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31719132, 28492532) -

Jan 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Jun 14, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R2240W variant (also known as c.6718C>T), located in coding exon 46 of the CACNA1A gene, results from a C to T substitution at nucleotide position 6718. The arginine at codon 2240 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is not well 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. -

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

Feb 24, 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	Benign	0.22
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.0077
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.2	.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.3	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.014	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.32
MutPred		0.37		.;.;Loss of methylation at R2240 (P = 0.0068);Loss of methylation at R2240 (P = 0.0068);Loss of methylation at R2240 (P = 0.0068);.;.;Loss of methylation at R2240 (P = 0.0068);.;.;.;.;Loss of methylation at R2240 (P = 0.0068);.;.;.;.;.;
MVP		0.90
MPC		0.83
ClinPred		0.63	D
GERP RS		2.9
Varity_R		0.17
gMVP		0.32

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: rs759576380; hg19: chr19-13319635;