19-13317310-C-T

Variant names:

• chr19-13317310-C-T
• rs41276886
• NM_001127222.2:c.1357G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127222.2(CACNA1A):​c.1357G>A​(p.Ala453Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00502 in 1,600,748 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A453S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (27 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 4.13
• Publications: 23 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

ENSG00000306107 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009932339).
• BP6: Variant 19-13317310-C-T is Benign according to our data. Variant chr19-13317310-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 68420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00425 (647/152144) while in subpopulation NFE AF = 0.00544 (370/68008). AF 95% confidence interval is 0.00498. There are 5 homozygotes in GnomAd4. There are 347 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 647 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.1357G>A	p.Ala453Thr	missense	Exon 11 of 47	NP_001120694.1	O00555-8
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.1360G>A	p.Ala454Thr	missense	Exon 11 of 47	NP_001120693.1	O00555-3
	CACNA1A	NM_023035.3		c.1360G>A	p.Ala454Thr	missense	Exon 11 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.1357G>A	p.Ala453Thr	missense	Exon 11 of 47	ENSP00000353362.5	O00555-8
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.1360G>A	p.Ala454Thr	missense	Exon 11 of 47	ENSP00000489913.1	O00555-3
	CACNA1A	ENST00000638029.1	TSL:5	c.1360G>A	p.Ala454Thr	missense	Exon 11 of 48	ENSP00000489829.1	A0A087WW63

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 647 AN: 152026 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000870

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00544

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00447 AC: 1108 AN: 247928 AF XY: 0.00431

Gnomad AFR exome AF: 0.000653

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.000400

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.00534

Gnomad OTH exome AF: 0.00600

GnomAD4 exome AF: 0.00510 AC: 7391 AN: 1448604 Hom.: 27 Cov.: 31 AF XY: 0.00492 AC XY: 3532 AN XY: 717536

African (AFR) AF: 0.000751 AC: 25 AN: 33278

American (AMR) AF: 0.00106 AC: 47 AN: 44448

Ashkenazi Jewish (ASJ) AF: 0.000346 AC: 9 AN: 25990

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39336

South Asian (SAS) AF: 0.000722 AC: 62 AN: 85898

European-Finnish (FIN) AF: 0.0187 AC: 994 AN: 53238

Middle Eastern (MID) AF: 0.000881 AC: 5 AN: 5674

European-Non Finnish (NFE) AF: 0.00547 AC: 6022 AN: 1100998

Other (OTH) AF: 0.00378 AC: 226 AN: 59744

GnomAD4 genome AF: 0.00425 AC: 647 AN: 152144 Hom.: 5 Cov.: 32 AF XY: 0.00467 AC XY: 347 AN XY: 74362

African (AFR) AF: 0.000867 AC: 36 AN: 41502

American (AMR) AF: 0.000851 AC: 13 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.0174 AC: 184 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00544 AC: 370 AN: 68008

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00464 Hom.: 7

Bravo AF: 0.00319

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00106 AC: 4

ESP6500EA AF: 0.00570 AC: 47

ExAC AF: 0.00440 AC: 532

EpiCase AF: 0.00453

EpiControl AF: 0.00333

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	not specified (4)
-	-	1	CACNA1A-related disorder (1)
-	-	1	Episodic ataxia type 2 (1)
-	-	1	Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0099	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.6	L
PhyloP100		4.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.56
Sift	Benign	0.34	T
Sift4G	Benign	0.082	T
Vest4		0.55
MVP		0.97
MPC		2.2
ClinPred		0.031	T
GERP RS		5.6
Varity_R		0.27
gMVP		0.70
Mutation Taster		=32/68	disease causing

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: rs41276886; hg19: chr19-13428124; COSMIC: COSV64202206; COSMIC: COSV64202206;