ENST00000636389.1:c.6832G>A

Variant names:

• chr19-13207997-C-T
• rs147221323
• ENST00000636389.1:c.6832G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 8/10 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
• Publications: 5 publications found

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]

CACNA1A Gene-Disease associations (from GenCC):

• episodic ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• developmental and epileptic encephalopathy, 42

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• migraine, familial hemiplegic, 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• benign paroxysmal torticollis of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300728 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId is 257512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000636389.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	NM_001127222.2	MANE Select	c.6837G>A	p.Pro2279Pro	synonymous	Exon 47 of 47	NP_001120694.1	O00555-8
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.*49G>A		3_prime_UTR	Exon 47 of 47	NP_001120693.1	O00555-3
	CACNA1A	NM_023035.3		c.6855G>A	p.Pro2285Pro	synonymous	Exon 48 of 48	NP_075461.2	A0A087WW63

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	ENST00000636389.1	TSL:5	c.6832G>A	p.Ala2278Thr	missense	Exon 47 of 47	ENSP00000489992.1	A0A1B0GU74
	CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.6837G>A	p.Pro2279Pro	synonymous	Exon 47 of 47	ENSP00000353362.5	O00555-8
	CACNA1A	ENST00000638029.1	TSL:5	c.6855G>A	p.Pro2285Pro	synonymous	Exon 48 of 48	ENSP00000489829.1	A0A087WW63

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

GnomAD2 exomes AF: 0.0492 AC: 702 AN: 14274 AF XY: 0.0484

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 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

African (AFR) AF: 0.00714 AC: 169 AN: 23682

American (AMR) AF: 0.0348 AC: 377 AN: 10834

Ashkenazi Jewish (ASJ) AF: 0.0525 AC: 854 AN: 16278

East Asian (EAS) AF: 0.000110 AC: 3 AN: 27338

South Asian (SAS) AF: 0.00913 AC: 392 AN: 42914

European-Finnish (FIN) AF: 0.0228 AC: 627 AN: 27452

Middle Eastern (MID) AF: 0.0164 AC: 74 AN: 4504

European-Non Finnish (NFE) AF: 0.0530 AC: 51645 AN: 974728

Other (OTH) AF: 0.0399 AC: 1930 AN: 48400

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

African (AFR) AF: 0.00939 AC: 387 AN: 41200

American (AMR) AF: 0.0385 AC: 586 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00748 AC: 36 AN: 4810

European-Finnish (FIN) AF: 0.0203 AC: 212 AN: 10452

Middle Eastern (MID) AF: 0.0105 AC: 3 AN: 286

European-Non Finnish (NFE) AF: 0.0511 AC: 3458 AN: 67732

Other (OTH) AF: 0.0367 AC: 77 AN: 2098

Alfa AF: 0.0420 Hom.: 146

Bravo AF: 0.0346

ESP6500AA AF: 0.00617 AC: 17

ESP6500EA AF: 0.0338 AC: 217

ExAC AF: 0.0107 AC: 882

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
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
PhyloP100		-1.4
GERP RS		0.42
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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