rs369033909

Positions:

chr19-13235199-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001127222.2(CACNA1A):c.5133+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 1,606,702 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.00032 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

CACNA1A
NM_001127222.2 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.65

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 links:

CACNA1A (HGNC:):

CACNA1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 19-13235199-C-T is Benign according to our data. Variant chr19-13235199-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283174.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000315 (48/152260) while in subpopulation AMR AF= 0.0019 (29/15300). AF 95% confidence interval is 0.00136. There are 1 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 linkuse as main transcript	c.5133+10G>A		intron_variant		ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000360228.11 linkuse as main transcript	c.5133+10G>A	intron_variant	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 linkuse as main transcript	c.5151+10G>A	intron_variant	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 linkuse as main transcript	c.5139+10G>A	intron_variant	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 linkuse as main transcript	c.5136+10G>A	intron_variant	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 linkuse as main transcript	c.5136+10G>A	intron_variant	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 linkuse as main transcript	c.5136+10G>A	intron_variant	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 linkuse as main transcript	c.4995+10G>A	intron_variant	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 linkuse as main transcript	c.5136+10G>A	intron_variant	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 linkuse as main transcript	c.5151+10G>A	intron_variant	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 linkuse as main transcript	c.5142+10G>A	intron_variant	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 linkuse as main transcript	c.5139+10G>A	intron_variant	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 linkuse as main transcript	c.5136+10G>A	intron_variant	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 linkuse as main transcript	c.5136+10G>A	intron_variant	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 linkuse as main transcript	c.5136+10G>A	intron_variant	5		ENSP00000489777.1	O00555-5

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000560

AC:

132

AN:

235706

Hom.:

AF XY:

0.000438

AC XY:

AN XY:

127824

show subpopulations

Gnomad AFR exome

AF:

0.000278

Gnomad AMR exome

AF:

0.00248

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000170

Gnomad FIN exome

AF:

0.0000476

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.00223

GnomAD4 exome

AF:

0.000305

AC:

444

AN:

1454442

Hom.:

Cov.:

AF XY:

0.000277

AC XY:

200

AN XY:

723048

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.00242

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000203

Gnomad4 SAS exome

AF:

0.000211

Gnomad4 FIN exome

AF:

0.0000754

Gnomad4 NFE exome

AF:

0.000252

Gnomad4 OTH exome

AF:

0.000415

GnomAD4 genome

AF:

0.000315

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00190

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000277

Hom.:

Bravo

AF:

0.000495

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 24, 2017

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.050

DANN

Benign

0.27

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over