19-13207166-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000713789.1(CACNA1A):n.*2847C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 896,776 control chromosomes in the GnomAD database, including 90,744 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 17903 hom., cov: 29)

Exomes 𝑓: 0.44 ( 72841 hom. )

Consequence

CACNA1A
ENST00000713789.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0930

Publications

16 publications found

Variant links:

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

CACNA1A links:

ENSG00000300728 (HGNC:):

ENSG00000300728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 19-13207166-G-T is Benign according to our data. Variant chr19-13207166-G-T is described in ClinVar as [Benign]. Clinvar id is 1292948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.*147C>A		3_prime_UTR_variant	Exon 47 of 47	ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000636768.2 link	n.*1929C>A	non_coding_transcript_exon_variant	Exon 45 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.*2847C>A	non_coding_transcript_exon_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000360228.11 link	c.*147C>A	3_prime_UTR_variant	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000637769.1 link	c.*147C>A	3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000637736.1 link	c.*147C>A	3_prime_UTR_variant	Exon 46 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.*754C>A	3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000635895.1 link	c.*880C>A	3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.*880C>A	3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000636768.2 link	n.*1929C>A	3_prime_UTR_variant	Exon 45 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.*2847C>A	3_prime_UTR_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000638029.1 link	c.*147C>A	downstream_gene_variant		5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.*147C>A	downstream_gene_variant		5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.*147C>A	downstream_gene_variant		5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000636012.1 link	c.*147C>A	downstream_gene_variant		5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637432.1 link	c.*880C>A	downstream_gene_variant		5		ENSP00000490617.1	O00555-2

Frequencies

GnomAD3 genomes

AF:

0.480

AC:

72581

AN:

151216

Hom.:

17877

Cov.:

show subpopulations

Gnomad AFR

AF:

0.574

Gnomad AMI

AF:

0.391

Gnomad AMR

AF:

0.507

Gnomad ASJ

AF:

0.530

Gnomad EAS

AF:

0.369

Gnomad SAS

AF:

0.585

Gnomad FIN

AF:

0.418

Gnomad MID

AF:

0.641

Gnomad NFE

AF:

0.424

Gnomad OTH

AF:

0.519

GnomAD4 exome

AF:

0.437

AC:

325472

AN:

745448

Hom.:

72841

Cov.:

AF XY:

0.443

AC XY:

166138

AN XY:

375138

show subpopulations

African (AFR)

AF:

0.585

AC:

7945

AN:

13572

American (AMR)

AF:

0.535

AC:

6168

AN:

11536

Ashkenazi Jewish (ASJ)

AF:

0.525

AC:

6759

AN:

12866

East Asian (EAS)

AF:

0.352

AC:

8397

AN:

23874

South Asian (SAS)

AF:

0.590

AC:

28474

AN:

48284

European-Finnish (FIN)

AF:

0.409

AC:

11567

AN:

28278

Middle Eastern (MID)

AF:

0.571

AC:

1391

AN:

2434

European-Non Finnish (NFE)

AF:

0.419

AC:

239339

AN:

571146

Other (OTH)

AF:

0.461

AC:

15432

AN:

33458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

8733

17465

26198

34930

43663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.480

AC:

72659

AN:

151328

Hom.:

17903

Cov.:

AF XY:

0.482

AC XY:

35633

AN XY:

73972

show subpopulations

African (AFR)

AF:

0.574

AC:

23693

AN:

41278

American (AMR)

AF:

0.507

AC:

7723

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.530

AC:

1835

AN:

3464

East Asian (EAS)

AF:

0.369

AC:

1889

AN:

5120

South Asian (SAS)

AF:

0.584

AC:

2800

AN:

4796

European-Finnish (FIN)

AF:

0.418

AC:

4357

AN:

10430

Middle Eastern (MID)

AF:

0.648

AC:

188

AN:

290

European-Non Finnish (NFE)

AF:

0.424

AC:

28717

AN:

67710

Other (OTH)

AF:

0.525

AC:

1103

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1841

3682

5523

7364

9205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.456

Hom.:

17632

Bravo

AF:

0.489

Asia WGS

AF:

0.552

AC:

1915

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.7

(source)

DANN

Benign

0.91

PhyloP100

-0.093

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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19-13207166-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over