rs16018

Variant names:

• chr19-13300668-G-A
• rs16018
• NM_001127222.2:c.2173-12C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13300668-G-A
• chr19-13300668-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127222.2(CACNA1A):​c.2173-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 1,608,152 control chromosomes in the GnomAD database, including 416,334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (35710 hom., cov: 31)
  • Exomes 𝑓: 0.72 (380624 hom.)
• Consequence: CACNA1A NM_001127222.2 intron
• Scores: Splicing: ADA: 0.00002687
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.528
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-13300668-G-A is Benign according to our data. Variant chr19-13300668-G-A is described in ClinVar as Benign. ClinVar VariationId is 257510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 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.2173-12C>T		intron	N/A	NP_001120694.1	O00555-8
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.2176-12C>T		intron	N/A	NP_001120693.1	O00555-3
	CACNA1A	NM_023035.3		c.2185-12C>T		intron	N/A	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.2173-12C>T		intron	N/A	ENSP00000353362.5	O00555-8
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.2176-12C>T		intron	N/A	ENSP00000489913.1	O00555-3
	CACNA1A	ENST00000638029.1	TSL:5	c.2185-12C>T		intron	N/A	ENSP00000489829.1	A0A087WW63

Frequencies

GnomAD3 genomes AF: 0.674 AC: 102301 AN: 151828 Hom.: 35690 Cov.: 31

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.693

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.853

Gnomad FIN AF: 0.793

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.680

GnomAD2 exomes AF: 0.755 AC: 188197 AN: 249270 AF XY: 0.757

Gnomad AFR exome AF: 0.499

Gnomad AMR exome AF: 0.840

Gnomad ASJ exome AF: 0.700

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.785

Gnomad NFE exome AF: 0.703

Gnomad OTH exome AF: 0.726

GnomAD4 exome AF: 0.719 AC: 1046691 AN: 1456206 Hom.: 380624 Cov.: 32 AF XY: 0.723 AC XY: 523830 AN XY: 724794

African (AFR) AF: 0.496 AC: 16538 AN: 33326

American (AMR) AF: 0.832 AC: 37200 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 18377 AN: 26100

East Asian (EAS) AF: 0.991 AC: 39311 AN: 39680

South Asian (SAS) AF: 0.839 AC: 72305 AN: 86162

European-Finnish (FIN) AF: 0.780 AC: 41623 AN: 53382

Middle Eastern (MID) AF: 0.661 AC: 3801 AN: 5754

European-Non Finnish (NFE) AF: 0.700 AC: 774340 AN: 1106900

Other (OTH) AF: 0.718 AC: 43196 AN: 60186

GnomAD4 genome AF: 0.674 AC: 102368 AN: 151946 Hom.: 35710 Cov.: 31 AF XY: 0.683 AC XY: 50750 AN XY: 74258

African (AFR) AF: 0.500 AC: 20716 AN: 41404

American (AMR) AF: 0.760 AC: 11597 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 2403 AN: 3466

East Asian (EAS) AF: 0.996 AC: 5155 AN: 5174

South Asian (SAS) AF: 0.852 AC: 4105 AN: 4818

European-Finnish (FIN) AF: 0.793 AC: 8383 AN: 10570

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.703 AC: 47739 AN: 67932

Other (OTH) AF: 0.684 AC: 1445 AN: 2114

Alfa AF: 0.697 Hom.: 85141

Bravo AF: 0.662

Asia WGS AF: 0.898 AC: 3121 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Developmental and epileptic encephalopathy, 42 (1)
-	-	1	Episodic ataxia type 2 (1)
-	-	1	Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 (1)
-	-	1	Migraine, familial hemiplegic, 1 (1)
-	-	1	not provided (1)
-	-	1	Spinocerebellar ataxia type 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.6
DANN	Benign	0.66
PhyloP100		0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0060
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: rs16018; hg19: chr19-13411482;