19-13286510-G-A

Variant names:

• chr19-13286510-G-A
• rs16029
• NM_001127222.2:c.3546C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001127222.2(CACNA1A):​c.3546C>T​(p.Val1182Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,368,834 control chromosomes in the GnomAD database, including 341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (36 hom., cov: 30)
  • Exomes 𝑓: 0.020 (305 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.594
• Publications: 8 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 19-13286510-G-A is Benign according to our data. Variant chr19-13286510-G-A is described in ClinVar as Benign. ClinVar VariationId is 93561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.594 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0173 (2612/151270) while in subpopulation NFE AF = 0.0274 (1857/67692). AF 95% confidence interval is 0.0264. There are 36 homozygotes in GnomAd4. There are 1274 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2612 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127222.2. 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.3546C>T	p.Val1182Val	synonymous	Exon 20 of 47	NP_001120694.1	O00555-8
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.3549C>T	p.Val1183Val	synonymous	Exon 20 of 47	NP_001120693.1	O00555-3
	CACNA1A	NM_023035.3		c.3558C>T	p.Val1186Val	synonymous	Exon 20 of 48	NP_075461.2	A0A087WW63

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.3546C>T	p.Val1182Val	synonymous	Exon 20 of 47	ENSP00000353362.5	O00555-8
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.3549C>T	p.Val1183Val	synonymous	Exon 20 of 47	ENSP00000489913.1	O00555-3
	CACNA1A	ENST00000638029.1	TSL:5	c.3558C>T	p.Val1186Val	synonymous	Exon 20 of 48	ENSP00000489829.1	A0A087WW63

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2611 AN: 151146 Hom.: 36 Cov.: 30

Gnomad AFR AF: 0.00373

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.00998

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.000392

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.0244

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0274

Gnomad OTH AF: 0.0154

GnomAD2 exomes AF: 0.0170 AC: 2890 AN: 169562 AF XY: 0.0178

Gnomad AFR exome AF: 0.00417

Gnomad AMR exome AF: 0.00916

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.000134

Gnomad FIN exome AF: 0.0256

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0196 AC: 23841 AN: 1217564 Hom.: 305 Cov.: 19 AF XY: 0.0197 AC XY: 11884 AN XY: 603788

African (AFR) AF: 0.00323 AC: 88 AN: 27250

American (AMR) AF: 0.0103 AC: 297 AN: 28700

Ashkenazi Jewish (ASJ) AF: 0.0146 AC: 275 AN: 18896

East Asian (EAS) AF: 0.000135 AC: 5 AN: 36930

South Asian (SAS) AF: 0.0126 AC: 825 AN: 65608

European-Finnish (FIN) AF: 0.0276 AC: 1342 AN: 48696

Middle Eastern (MID) AF: 0.0112 AC: 56 AN: 5016

European-Non Finnish (NFE) AF: 0.0214 AC: 20032 AN: 935242

Other (OTH) AF: 0.0180 AC: 921 AN: 51226

GnomAD4 genome AF: 0.0173 AC: 2612 AN: 151270 Hom.: 36 Cov.: 30 AF XY: 0.0172 AC XY: 1274 AN XY: 73914

African (AFR) AF: 0.00372 AC: 154 AN: 41370

American (AMR) AF: 0.00997 AC: 152 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0188 AC: 65 AN: 3454

East Asian (EAS) AF: 0.000392 AC: 2 AN: 5096

South Asian (SAS) AF: 0.0149 AC: 71 AN: 4770

European-Finnish (FIN) AF: 0.0244 AC: 252 AN: 10326

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0274 AC: 1857 AN: 67692

Other (OTH) AF: 0.0152 AC: 32 AN: 2106

Alfa AF: 0.0221 Hom.: 33

Bravo AF: 0.0143

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	1	Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	1.3
DANN	Benign	0.69
PhyloP100		-0.59
Mutation Taster		=97/3	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: rs16029; hg19: chr19-13397324; COSMIC: COSV64190077; COSMIC: COSV64190077;