19-13207997-C-T

Position:

• chr19-13207997-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The ENST00000636389.1(CACNA1A):​c.6832G>A​(p.Ala2278Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.046 in 1,327,418 control chromosomes in the GnomAD database, including 1,692 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2278A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.033 (99 hom., cov: 29)
  • Exomes 𝑓: 0.048 (1593 hom.)
• Consequence: CACNA1A ENST00000636389.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.42

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 Benign. Variant got -19 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 5.1862 (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=0.001943469).
• BP6: Variant 19-13207997-C-T is Benign according to our data. Variant chr19-13207997-C-T is described in ClinVar as [Benign]. Clinvar id is 257512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13207997-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6837G>A	p.Pro2279Pro	synonymous_variant	47/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000636389.1	c.6832G>A	p.Ala2278Thr	missense_variant	47/47	5		ENSP00000489992.1
CACNA1A	ENST00000360228.11	c.6837G>A	p.Pro2279Pro	synonymous_variant	47/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6855G>A	p.Pro2285Pro	synonymous_variant	48/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6843G>A	p.Pro2281Pro	synonymous_variant	47/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6840G>A	p.Pro2280Pro	synonymous_variant	47/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6840G>A	p.Pro2280Pro	synonymous_variant	47/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6804G>A	p.Pro2268Pro	synonymous_variant	46/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6699G>A	p.Pro2233Pro	synonymous_variant	46/46	5		ENSP00000489861.1
CACNA1A	ENST00000637432	c.*49G>A		3_prime_UTR_variant	48/48	5		ENSP00000490617.1
CACNA1A	ENST00000635895	c.*49G>A		3_prime_UTR_variant	47/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009	c.*49G>A		3_prime_UTR_variant	47/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276	c.*49G>A		3_prime_UTR_variant	46/46	5		ENSP00000489777.1
CACNA1A	ENST00000636549.1	c.*49G>A		downstream_gene_variant		5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.*49G>A		downstream_gene_variant		5		ENSP00000489715.1

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 4979 AN: 151182 Hom.: 99 Cov.: 29

Gnomad AFR AF: 0.00942

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.0386

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00748

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.0511

Gnomad OTH AF: 0.0371

GnomAD3 exomes AF: 0.0492 AC: 702 AN: 14274 Hom.: 33 AF XY: 0.0484 AC XY: 363 AN XY: 7504

Gnomad AFR exome AF: 0.00851

Gnomad AMR exome AF: 0.0452

Gnomad ASJ exome AF: 0.0911

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0175

Gnomad FIN exome AF: 0.0273

Gnomad NFE exome AF: 0.0591

Gnomad OTH exome AF: 0.0428

GnomAD4 exome AF: 0.0477 AC: 56071 AN: 1176130 Hom.: 1593 Cov.: 34 AF XY: 0.0470 AC XY: 26636 AN XY: 566304

Gnomad4 AFR exome AF: 0.00714

Gnomad4 AMR exome AF: 0.0348

Gnomad4 ASJ exome AF: 0.0525

Gnomad4 EAS exome AF: 0.000110

Gnomad4 SAS exome AF: 0.00913

Gnomad4 FIN exome AF: 0.0228

Gnomad4 NFE exome AF: 0.0530

Gnomad4 OTH exome AF: 0.0399

GnomAD4 genome AF: 0.0329 AC: 4976 AN: 151288 Hom.: 99 Cov.: 29 AF XY: 0.0301 AC XY: 2222 AN XY: 73914

Gnomad4 AFR AF: 0.00939

Gnomad4 AMR AF: 0.0385

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00748

Gnomad4 FIN AF: 0.0203

Gnomad4 NFE AF: 0.0511

Gnomad4 OTH AF: 0.0367

Alfa AF: 0.0449 Hom.: 97

Bravo AF: 0.0346

ESP6500AA AF: 0.00617 AC: 17

ESP6500EA AF: 0.0338 AC: 217

ExAC AF: 0.0107 AC: 882

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.2
DANN	Benign	0.95
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0019	T
GERP RS		0.42

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: rs147221323; hg19: chr19-13318811; COSMIC: COSV64196706; COSMIC: COSV64196706;