rs758625682

Positions:

• chr19-13208785-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP6 BS2

The NM_001127222.2(CACNA1A):​c.6751G>A​(p.Glu2251Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000148 in 1,553,364 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 0.000047 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.57

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 -4 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.
• BP6: Variant 19-13208785-C-T is Benign according to our data. Variant chr19-13208785-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 579755.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6751G>A	p.Glu2251Lys	missense_variant	46/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6751G>A	p.Glu2251Lys	missense_variant	46/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6769G>A	p.Glu2257Lys	missense_variant	47/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6757G>A	p.Glu2253Lys	missense_variant	46/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6754G>A	p.Glu2252Lys	missense_variant	46/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6754G>A	p.Glu2252Lys	missense_variant	46/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6718G>A	p.Glu2240Lys	missense_variant	45/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6613G>A	p.Glu2205Lys	missense_variant	45/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6754G>A	p.Glu2252Lys	missense_variant	46/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6769G>A	p.Glu2257Lys	missense_variant	47/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6760G>A	p.Glu2254Lys	missense_variant	47/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6757G>A	p.Glu2253Lys	missense_variant	46/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6754G>A	p.Glu2252Lys	missense_variant	46/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6754G>A	p.Glu2252Lys	missense_variant	46/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6718G>A	p.Glu2240Lys	missense_variant	45/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.0000468 AC: 7 AN: 149708 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000171

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000113 AC: 2 AN: 176608 Hom.: 0 AF XY: 0.0000102 AC XY: 1 AN XY: 98390

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: 0.0000388

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000114 AC: 16 AN: 1403656 Hom.: 0 Cov.: 33 AF XY: 0.0000129 AC XY: 9 AN XY: 695710

Gnomad4 AFR exome AF: 0.0000620

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000101

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.0000468 AC: 7 AN: 149708 Hom.: 0 Cov.: 31 AF XY: 0.0000410 AC XY: 3 AN XY: 73110

Gnomad4 AFR AF: 0.000171

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000604

ExAC AF: 0.0000264 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 19, 2021

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 -

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

May 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	2.9	.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-2.1	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.55
Sift	Benign	0.057	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.57	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.55
MutPred		0.34		.;.;Gain of methylation at E2252 (P = 0.0101);Gain of methylation at E2252 (P = 0.0101);Gain of methylation at E2252 (P = 0.0101);.;.;Gain of methylation at E2252 (P = 0.0101);.;.;.;.;Gain of methylation at E2252 (P = 0.0101);.;.;.;.;.;
MVP		0.91
MPC		0.61
ClinPred		0.75	D
GERP RS		3.9
Varity_R		0.19
gMVP		0.34

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: rs758625682; hg19: chr19-13319599;