rs751044309

Positions:

• chr19-13209389-C-T

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.6449G>A​(p.Arg2150Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,396,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.16

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]

CACNA1A (HGNC:):

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=0.122974634).
• BP6: Variant 19-13209389-C-T is Benign according to our data. Variant chr19-13209389-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542823.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6449G>A	p.Arg2150Gln	missense_variant	45/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6449G>A	p.Arg2150Gln	missense_variant	45/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6467G>A	p.Arg2156Gln	missense_variant	46/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6455G>A	p.Arg2152Gln	missense_variant	45/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6452G>A	p.Arg2151Gln	missense_variant	45/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6452G>A	p.Arg2151Gln	missense_variant	45/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6416G>A	p.Arg2139Gln	missense_variant	44/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6311G>A	p.Arg2104Gln	missense_variant	44/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6452G>A	p.Arg2151Gln	missense_variant	45/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6467G>A	p.Arg2156Gln	missense_variant	46/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6458G>A	p.Arg2153Gln	missense_variant	46/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6455G>A	p.Arg2152Gln	missense_variant	45/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6452G>A	p.Arg2151Gln	missense_variant	45/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6452G>A	p.Arg2151Gln	missense_variant	45/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6416G>A	p.Arg2139Gln	missense_variant	44/46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*715G>A		non_coding_transcript_exon_variant	9/10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*715G>A		3_prime_UTR_variant	9/10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000556 AC: 3 AN: 53944 Hom.: 0 AF XY: 0.0000730 AC XY: 2 AN XY: 27408

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000938

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000737

GnomAD4 exome AF: 0.0000169 AC: 21 AN: 1244070 Hom.: 0 Cov.: 32 AF XY: 0.0000183 AC XY: 11 AN XY: 601148

Gnomad4 AFR exome AF: 0.00

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: 0.0000231

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000197

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.00000897 AC: 1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.6452G>A (p.R2151Q) alteration is located in exon 45 (coding exon 45) of the CACNA1A gene. This alteration results from a G to A substitution at nucleotide position 6452, causing the arginine (R) at amino acid position 2151 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

CACNA1A: PP2 -

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

Oct 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.2	.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.6	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.13	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.24	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.22
MutPred		0.27		.;.;Loss of catalytic residue at R2151 (P = 0.0265);Loss of catalytic residue at R2151 (P = 0.0265);Loss of catalytic residue at R2151 (P = 0.0265);.;.;Loss of catalytic residue at R2151 (P = 0.0265);.;.;.;.;Loss of catalytic residue at R2151 (P = 0.0265);.;.;.;.;.;
MVP		0.81
MPC		0.33
ClinPred		0.12	T
GERP RS		2.3
Varity_R		0.12
gMVP		0.28

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: rs751044309; hg19: chr19-13320203;