chr19-13365402-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_001127222.2(CACNA1A):c.699A>G(p.Leu233Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -1.25

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 19-13365402-T-C is Benign according to our data. Variant chr19-13365402-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 500577.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BP7

Synonymous conserved (PhyloP=-1.25 with no splicing effect.

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.699A>G	p.Leu233Leu	synonymous_variant	Exon 5 of 47	ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000360228.11 link	c.699A>G	p.Leu233Leu	synonymous_variant	Exon 5 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.699A>G	p.Leu233Leu	synonymous_variant	Exon 5 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.699A>G	p.Leu233Leu	synonymous_variant	Exon 5 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.699A>G	p.Leu233Leu	synonymous_variant	Exon 5 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.699A>G	p.Leu233Leu	synonymous_variant	Exon 5 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.699A>G	p.Leu233Leu	synonymous_variant	Exon 5 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.558A>G	p.Leu186Leu	synonymous_variant	Exon 4 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.699A>G	p.Leu233Leu	synonymous_variant	Exon 5 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.699A>G	p.Leu233Leu	synonymous_variant	Exon 5 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.699A>G	p.Leu233Leu	synonymous_variant	Exon 5 of 48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.699A>G	p.Leu233Leu	synonymous_variant	Exon 5 of 47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.699A>G	p.Leu233Leu	synonymous_variant	Exon 5 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.699A>G	p.Leu233Leu	synonymous_variant	Exon 5 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.699A>G	p.Leu233Leu	synonymous_variant	Exon 5 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.2 link	n.699A>G		non_coding_transcript_exon_variant	Exon 5 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.699A>G		non_coding_transcript_exon_variant	Exon 5 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151720

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000803

AC:

AN:

249050

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461422

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727018

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111686

Other (OTH)

AF:

0.0000166

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151720

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74048

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41260

American (AMR)

AF:

0.0000657

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 08, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Oct 04, 2023

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42

Benign:1

May 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.8

(source)

DANN

Benign

0.63

PhyloP100

-1.3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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