rs16016

Variant names:

• chr19-13303780-C-T
• rs16016
• NM_001127222.2:c.2091G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-13303780-C-T
• chr19-13303780-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001127222.2(CACNA1A):​c.2091G>A​(p.Thr697Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,608,958 control chromosomes in the GnomAD database, including 18,209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1447 hom., cov: 29)
  • Exomes 𝑓: 0.14 (16762 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.00
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-13303780-C-T is Benign according to our data. Variant chr19-13303780-C-T is described in ClinVar as Benign. ClinVar VariationId is 128546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

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.2091G>A	p.Thr697Thr	synonymous	Exon 16 of 47	NP_001120694.1	O00555-8
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.2094G>A	p.Thr698Thr	synonymous	Exon 16 of 47	NP_001120693.1	O00555-3
	CACNA1A	NM_023035.3		c.2094G>A	p.Thr698Thr	synonymous	Exon 16 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.2091G>A	p.Thr697Thr	synonymous	Exon 16 of 47	ENSP00000353362.5	O00555-8
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.2094G>A	p.Thr698Thr	synonymous	Exon 16 of 47	ENSP00000489913.1	O00555-3
	CACNA1A	ENST00000638029.1	TSL:5	c.2094G>A	p.Thr698Thr	synonymous	Exon 16 of 48	ENSP00000489829.1	A0A087WW63

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19329 AN: 151852 Hom.: 1441 Cov.: 29

Gnomad AFR AF: 0.0832

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.165 AC: 41049 AN: 249262 AF XY: 0.167

Gnomad AFR exome AF: 0.0814

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.304

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.143 AC: 207901 AN: 1456986 Hom.: 16762 Cov.: 31 AF XY: 0.146 AC XY: 105703 AN XY: 725134

African (AFR) AF: 0.0829 AC: 2767 AN: 33386

American (AMR) AF: 0.220 AC: 9841 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 3556 AN: 26108

East Asian (EAS) AF: 0.302 AC: 11988 AN: 39678

South Asian (SAS) AF: 0.258 AC: 22256 AN: 86138

European-Finnish (FIN) AF: 0.116 AC: 6192 AN: 53382

Middle Eastern (MID) AF: 0.108 AC: 620 AN: 5764

European-Non Finnish (NFE) AF: 0.128 AC: 141795 AN: 1107620

Other (OTH) AF: 0.148 AC: 8886 AN: 60202

GnomAD4 genome AF: 0.127 AC: 19358 AN: 151972 Hom.: 1447 Cov.: 29 AF XY: 0.130 AC XY: 9675 AN XY: 74260

African (AFR) AF: 0.0834 AC: 3455 AN: 41450

American (AMR) AF: 0.166 AC: 2534 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 441 AN: 3466

East Asian (EAS) AF: 0.304 AC: 1563 AN: 5142

South Asian (SAS) AF: 0.267 AC: 1280 AN: 4794

European-Finnish (FIN) AF: 0.112 AC: 1180 AN: 10582

Middle Eastern (MID) AF: 0.103 AC: 30 AN: 292

European-Non Finnish (NFE) AF: 0.125 AC: 8493 AN: 67966

Other (OTH) AF: 0.137 AC: 288 AN: 2106

Alfa AF: 0.128 Hom.: 4446

Bravo AF: 0.130

Asia WGS AF: 0.331 AC: 1148 AN: 3478

EpiCase AF: 0.124

EpiControl AF: 0.123

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	-0.84
CADD	Benign	0.24
DANN	Benign	0.50
PhyloP100		-2.0
Mutation Taster		=75/25	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs16016; hg19: chr19-13414594; COSMIC: COSV64192873; COSMIC: COSV64192873;