19-13286592-T-C

Position:

• chr19-13286592-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BP6

The NM_001127222.2(CACNA1A):​c.3464A>G​(p.Asn1155Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,390,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: not found (cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.843

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.15288663).
• BP6: Variant 19-13286592-T-C is Benign according to our data. Variant chr19-13286592-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 664992.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3464A>G	p.Asn1155Ser	missense_variant	20/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3464A>G	p.Asn1155Ser	missense_variant	20/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3476A>G	p.Asn1159Ser	missense_variant	20/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3470A>G	p.Asn1157Ser	missense_variant	20/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3467A>G	p.Asn1156Ser	missense_variant	20/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3467A>G	p.Asn1156Ser	missense_variant	20/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3467A>G	p.Asn1156Ser	missense_variant	20/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3326A>G	p.Asn1109Ser	missense_variant	19/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3467A>G	p.Asn1156Ser	missense_variant	20/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3476A>G	p.Asn1159Ser	missense_variant	20/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3467A>G	p.Asn1156Ser	missense_variant	20/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3470A>G	p.Asn1157Ser	missense_variant	20/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3467A>G	p.Asn1156Ser	missense_variant	20/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3467A>G	p.Asn1156Ser	missense_variant	20/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3467A>G	p.Asn1156Ser	missense_variant	20/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.0000107 AC: 2 AN: 187546 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 99784

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000822

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1390118 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 685772

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000597

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

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

Nov 01, 2023

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

Aug 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.016	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.6	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.053
Sift	Benign	0.031	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.64	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.18
MutPred		0.18		.;.;Gain of glycosylation at N1156 (P = 0.0128);Gain of glycosylation at N1156 (P = 0.0128);Gain of glycosylation at N1156 (P = 0.0128);.;Gain of glycosylation at N1156 (P = 0.0128);.;.;Gain of glycosylation at N1156 (P = 0.0128);Gain of glycosylation at N1156 (P = 0.0128);.;Gain of glycosylation at N1156 (P = 0.0128);.;Gain of glycosylation at N1156 (P = 0.0128);
MVP		0.59
MPC		0.064
ClinPred		0.15	T
GERP RS		2.1
Varity_R		0.15
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: rs992828062; hg19: chr19-13397406;