chr19-13286878-G-A

Position:

• chr19-13286878-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4 BP6_Moderate BS2

The NM_001127222.2(CACNA1A):​c.3178C>T​(p.Pro1060Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.66

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 -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). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. GenCC has associacion of the 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=0.39107397).
• BP6: Variant 19-13286878-G-A is Benign according to our data. Variant chr19-13286878-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 476250.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3178C>T	p.Pro1060Ser	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.3178C>T	p.Pro1060Ser	missense_variant	20/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3190C>T	p.Pro1064Ser	missense_variant	20/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3184C>T	p.Pro1062Ser	missense_variant	20/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3181C>T	p.Pro1061Ser	missense_variant	20/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3181C>T	p.Pro1061Ser	missense_variant	20/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3181C>T	p.Pro1061Ser	missense_variant	20/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3040C>T	p.Pro1014Ser	missense_variant	19/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3181C>T	p.Pro1061Ser	missense_variant	20/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3190C>T	p.Pro1064Ser	missense_variant	20/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3181C>T	p.Pro1061Ser	missense_variant	20/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3184C>T	p.Pro1062Ser	missense_variant	20/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3181C>T	p.Pro1061Ser	missense_variant	20/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3181C>T	p.Pro1061Ser	missense_variant	20/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3181C>T	p.Pro1061Ser	missense_variant	20/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000162 AC: 4 AN: 246176 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134248

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.00000479 AC: 7 AN: 1461356 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 726980

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

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: 0.0000331

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jul 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	.;T;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.0021
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.6	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.9	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.11	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.28	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.52
MutPred		0.23		.;.;Loss of catalytic residue at P1060 (P = 0.0101);Loss of catalytic residue at P1060 (P = 0.0101);Loss of catalytic residue at P1060 (P = 0.0101);.;Loss of catalytic residue at P1060 (P = 0.0101);.;.;Loss of catalytic residue at P1060 (P = 0.0101);Loss of catalytic residue at P1060 (P = 0.0101);.;Loss of catalytic residue at P1060 (P = 0.0101);.;Loss of catalytic residue at P1060 (P = 0.0101);
MVP		0.81
MPC		0.085
ClinPred		0.44	T
GERP RS		5.2
Varity_R		0.12
gMVP		0.36

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: rs969592968; hg19: chr19-13397692;