19-13298896-G-C

Position:

• chr19-13298896-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001127222.2(CACNA1A):​c.2737C>G​(p.Pro913Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000439 in 1,594,572 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P913S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.98

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 -5 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=0.20132005).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2737C>G	p.Pro913Ala	missense_variant	19/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2737C>G	p.Pro913Ala	missense_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2749C>G	p.Pro917Ala	missense_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2743C>G	p.Pro915Ala	missense_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2740C>G	p.Pro914Ala	missense_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2740C>G	p.Pro914Ala	missense_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2740C>G	p.Pro914Ala	missense_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2599C>G	p.Pro867Ala	missense_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2740C>G	p.Pro914Ala	missense_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2749C>G	p.Pro917Ala	missense_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2740C>G	p.Pro914Ala	missense_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2743C>G	p.Pro915Ala	missense_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2740C>G	p.Pro914Ala	missense_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2740C>G	p.Pro914Ala	missense_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2740C>G	p.Pro914Ala	missense_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32

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

GnomAD4 exome AF: 0.00000416 AC: 6 AN: 1442344 Hom.: 0 Cov.: 32 AF XY: 0.00000557 AC XY: 4 AN XY: 717848

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: 0.00

Gnomad4 NFE exome AF: 0.00000541

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74370

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Benign	0.47
DEOGEN2	Benign	0.030	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.73	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.69	.;.;.;.;N;.;.;.;.;.;.;.;N;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.1	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.20	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.80	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.14
MutPred		0.17		.;.;Loss of catalytic residue at L911 (P = 0.2399);Loss of catalytic residue at L911 (P = 0.2399);Loss of catalytic residue at L911 (P = 0.2399);.;Loss of catalytic residue at L911 (P = 0.2399);.;.;Loss of catalytic residue at L911 (P = 0.2399);Loss of catalytic residue at L911 (P = 0.2399);.;Loss of catalytic residue at L911 (P = 0.2399);.;Loss of catalytic residue at L911 (P = 0.2399);
MVP		0.75
MPC		1.1
ClinPred		0.095	T
GERP RS		3.2
Varity_R		0.11
gMVP		0.46

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: rs16020; hg19: chr19-13409710;