rs969592968

Positions:

• 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). 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=0.39107397).
• 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;