19-13298658-T-A

Variant names:

• chr19-13298658-T-A
• rs16023
• NM_001127222.2:c.2975A>T

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.2975A>T​(p.Glu992Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,502,488 control chromosomes in the GnomAD database, including 15,900 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E992Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.13 (1408 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14492 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 2.84
• Publications: 22 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: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

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

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

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• 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 (MetaRNN=0.0017878115).
• BP6: Variant 19-13298658-T-A is Benign according to our data. Variant chr19-13298658-T-A is described in ClinVar as Benign. ClinVar VariationId is 68427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.148 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	NM_001127222.2	MANE Select	c.2975A>T	p.Glu992Val	missense	Exon 19 of 47	NP_001120694.1
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.2978A>T	p.Glu993Val	missense	Exon 19 of 47	NP_001120693.1
	CACNA1A	NM_023035.3		c.2987A>T	p.Glu996Val	missense	Exon 19 of 48	NP_075461.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.2975A>T	p.Glu992Val	missense	Exon 19 of 47	ENSP00000353362.5
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.2978A>T	p.Glu993Val	missense	Exon 19 of 47	ENSP00000489913.1
	CACNA1A	ENST00000638029.1	TSL:5	c.2987A>T	p.Glu996Val	missense	Exon 19 of 48	ENSP00000489829.1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20277 AN: 151782 Hom.: 1410 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.137 AC: 14100 AN: 102910 AF XY: 0.134

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.0934

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.144 AC: 194404 AN: 1350598 Hom.: 14492 Cov.: 32 AF XY: 0.144 AC XY: 95757 AN XY: 666138

African (AFR) AF: 0.0978 AC: 2641 AN: 27012

American (AMR) AF: 0.147 AC: 4253 AN: 28944

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 3820 AN: 23430

East Asian (EAS) AF: 0.153 AC: 4545 AN: 29706

South Asian (SAS) AF: 0.116 AC: 8669 AN: 74636

European-Finnish (FIN) AF: 0.121 AC: 5745 AN: 47320

Middle Eastern (MID) AF: 0.202 AC: 1109 AN: 5500

European-Non Finnish (NFE) AF: 0.147 AC: 155295 AN: 1058490

Other (OTH) AF: 0.150 AC: 8327 AN: 55560

GnomAD4 genome AF: 0.133 AC: 20272 AN: 151890 Hom.: 1408 Cov.: 32 AF XY: 0.132 AC XY: 9802 AN XY: 74268

African (AFR) AF: 0.104 AC: 4330 AN: 41470

American (AMR) AF: 0.141 AC: 2145 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 558 AN: 3466

East Asian (EAS) AF: 0.123 AC: 629 AN: 5130

South Asian (SAS) AF: 0.120 AC: 578 AN: 4830

European-Finnish (FIN) AF: 0.123 AC: 1293 AN: 10518

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.151 AC: 10226 AN: 67908

Other (OTH) AF: 0.148 AC: 312 AN: 2108

Alfa AF: 0.145 Hom.: 532

Bravo AF: 0.135

TwinsUK AF: 0.138 AC: 512

ALSPAC AF: 0.146 AC: 563

ESP6500AA AF: 0.0930 AC: 230

ESP6500EA AF: 0.128 AC: 655

ExAC AF: 0.112 AC: 2507

Asia WGS AF: 0.113 AC: 392 AN: 3466

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	1	Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.28
Sift	Uncertain	0.029	D
Sift4G	Benign	0.16	T
Vest4		0.094
MPC		2.0
ClinPred		0.016	T
GERP RS		3.9
Varity_R		0.17
gMVP		0.52
Mutation Taster		=91/9	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: rs16023; hg19: chr19-13409472; COSMIC: COSV64201171;