rs16042

Variant names:

• chr19-13230223-G-A
• rs16042
• NM_001127222.2:c.5401-14C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13230223-G-A
• chr19-13230223-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.5401-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,612,806 control chromosomes in the GnomAD database, including 26,312 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3028 hom., cov: 31)
  • Exomes 𝑓: 0.15 (23284 hom.)
• Consequence: CACNA1A NM_001127222.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.181
• Publications: 12 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=-0.84).
• BP6: Variant 19-13230223-G-A is Benign according to our data. Variant chr19-13230223-G-A is described in ClinVar as Benign. ClinVar VariationId is 257511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.627 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.5401-14C>T		intron	N/A	NP_001120694.1	O00555-8
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.5404-14C>T		intron	N/A	NP_001120693.1	O00555-3
	CACNA1A	NM_023035.3		c.5419-14C>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.5401-14C>T		intron	N/A	ENSP00000353362.5	O00555-8
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.5404-14C>T		intron	N/A	ENSP00000489913.1	O00555-3
	CACNA1A	ENST00000638029.1	TSL:5	c.5419-14C>T		intron	N/A	ENSP00000489829.1	A0A087WW63

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26050 AN: 151874 Hom.: 3031 Cov.: 31

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.645

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.0941

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.168

GnomAD2 exomes AF: 0.200 AC: 49551 AN: 248370 AF XY: 0.195

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.277

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.642

Gnomad FIN exome AF: 0.0991

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.163

GnomAD4 exome AF: 0.154 AC: 225038 AN: 1460814 Hom.: 23284 Cov.: 32 AF XY: 0.155 AC XY: 112813 AN XY: 726716

African (AFR) AF: 0.178 AC: 5951 AN: 33466

American (AMR) AF: 0.273 AC: 12187 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 3457 AN: 26094

East Asian (EAS) AF: 0.610 AC: 24201 AN: 39680

South Asian (SAS) AF: 0.230 AC: 19826 AN: 86206

European-Finnish (FIN) AF: 0.102 AC: 5448 AN: 53348

Middle Eastern (MID) AF: 0.119 AC: 684 AN: 5764

European-Non Finnish (NFE) AF: 0.128 AC: 142738 AN: 1111296

Other (OTH) AF: 0.175 AC: 10546 AN: 60338

GnomAD4 genome AF: 0.171 AC: 26060 AN: 151992 Hom.: 3028 Cov.: 31 AF XY: 0.176 AC XY: 13066 AN XY: 74270

African (AFR) AF: 0.176 AC: 7309 AN: 41430

American (AMR) AF: 0.230 AC: 3510 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 497 AN: 3470

East Asian (EAS) AF: 0.645 AC: 3323 AN: 5150

South Asian (SAS) AF: 0.248 AC: 1195 AN: 4816

European-Finnish (FIN) AF: 0.0941 AC: 995 AN: 10578

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8793 AN: 67998

Other (OTH) AF: 0.168 AC: 353 AN: 2096

Alfa AF: 0.144 Hom.: 5628

Bravo AF: 0.185

Asia WGS AF: 0.411 AC: 1426 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.0
DANN	Benign	0.74
PhyloP100		-0.18
Mutation Taster		=100/0	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: rs16042; hg19: chr19-13341037; COSMIC: COSV64213397; COSMIC: COSV64213397;