19-13298836-C-T

Position:

• chr19-13298836-C-T

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.2797G>A​(p.Val933Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000886 in 1,580,876 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000091 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0330

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). 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=0.18196651).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2797G>A	p.Val933Met	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.2797G>A	p.Val933Met	missense_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2809G>A	p.Val937Met	missense_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2803G>A	p.Val935Met	missense_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2800G>A	p.Val934Met	missense_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2800G>A	p.Val934Met	missense_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2800G>A	p.Val934Met	missense_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2659G>A	p.Val887Met	missense_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2800G>A	p.Val934Met	missense_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2809G>A	p.Val937Met	missense_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2800G>A	p.Val934Met	missense_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2803G>A	p.Val935Met	missense_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2800G>A	p.Val934Met	missense_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2800G>A	p.Val934Met	missense_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2800G>A	p.Val934Met	missense_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 33

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: 0.00000910 AC: 13 AN: 1428676 Hom.: 0 Cov.: 32 AF XY: 0.00000986 AC XY: 7 AN XY: 709996

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: 0.0000118

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74356

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

Bravo AF: 0.00000378

ExAC AF: 0.00000873 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	14
DANN	Benign	0.84
DEOGEN2	Benign	0.0094	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.013	N
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.035	T
MutationAssessor	Benign	0.34	.;.;.;.;N;.;.;.;.;.;.;.;N;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.10	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.15	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.24	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.11
MutPred		0.16		.;.;Gain of MoRF binding (P = 0.2623);Gain of MoRF binding (P = 0.2623);Gain of MoRF binding (P = 0.2623);.;Gain of MoRF binding (P = 0.2623);.;.;Gain of MoRF binding (P = 0.2623);Gain of MoRF binding (P = 0.2623);.;Gain of MoRF binding (P = 0.2623);.;Gain of MoRF binding (P = 0.2623);
MVP		0.78
MPC		1.1
ClinPred		0.063	T
GERP RS		-0.75
Varity_R		0.036
gMVP		0.30

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: rs767187794; hg19: chr19-13409650; COSMIC: COSV64190238;