rs16042

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001127222.2(CACNA1A):c.5401-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,612,806 control chromosomes in the GnomAD database, including 26,312 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 3028 hom., cov: 31)

Exomes 𝑓: 0.15 ( 23284 hom. )

Consequence

CACNA1A
NM_001127222.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.181

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 19-13230223-G-A is Benign according to our data. Variant chr19-13230223-G-A is described in ClinVar as [Benign]. Clinvar id is 257511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13230223-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.5401-14C>T		intron_variant	Intron 35 of 46	ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000360228.11 link	c.5401-14C>T	intron_variant	Intron 35 of 46	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.5419-14C>T	intron_variant	Intron 36 of 47	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.5407-14C>T	intron_variant	Intron 35 of 46	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.5404-14C>T	intron_variant	Intron 35 of 46	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.5404-14C>T	intron_variant	Intron 35 of 46	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.5404-14C>T	intron_variant	Intron 35 of 45	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.5263-14C>T	intron_variant	Intron 34 of 45	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.5404-14C>T	intron_variant	Intron 35 of 46	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.5419-14C>T	intron_variant	Intron 36 of 47	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.5410-14C>T	intron_variant	Intron 36 of 47	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.5407-14C>T	intron_variant	Intron 35 of 46	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.5404-14C>T	intron_variant	Intron 35 of 46	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.5404-14C>T	intron_variant	Intron 35 of 46	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.5404-14C>T	intron_variant	Intron 35 of 45	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.1 link	n.28-14C>T	intron_variant	Intron 1 of 9	5		ENSP00000490190.2	A0A1B0GUP3

Frequencies

GnomAD3 genomes

AF:

0.172

AC:

26050

AN:

151874

Hom.:

3031

Cov.:

show subpopulations

Gnomad AFR

AF:

0.177

Gnomad AMI

AF:

0.0636

Gnomad AMR

AF:

0.229

Gnomad ASJ

AF:

0.143

Gnomad EAS

AF:

0.645

Gnomad SAS

AF:

0.248

Gnomad FIN

AF:

0.0941

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.168

GnomAD3 exomes

AF:

0.200

AC:

49551

AN:

248370

Hom.:

7404

AF XY:

0.195

AC XY:

26274

AN XY:

134810

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.277

Gnomad ASJ exome

AF:

0.137

Gnomad EAS exome

AF:

0.642

Gnomad SAS exome

AF:

0.231

Gnomad FIN exome

AF:

0.0991

Gnomad NFE exome

AF:

0.126

Gnomad OTH exome

AF:

0.163

GnomAD4 exome

AF:

0.154

AC:

225038

AN:

1460814

Hom.:

23284

Cov.:

AF XY:

0.155

AC XY:

112813

AN XY:

726716

show subpopulations

Gnomad4 AFR exome

AF:

0.178

Gnomad4 AMR exome

AF:

0.273

Gnomad4 ASJ exome

AF:

0.132

Gnomad4 EAS exome

AF:

0.610

Gnomad4 SAS exome

AF:

0.230

Gnomad4 FIN exome

AF:

0.102

Gnomad4 NFE exome

AF:

0.128

Gnomad4 OTH exome

AF:

0.175

GnomAD4 genome

AF:

0.171

AC:

26060

AN:

151992

Hom.:

3028

Cov.:

AF XY:

0.176

AC XY:

13066

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.176

Gnomad4 AMR

AF:

0.230

Gnomad4 ASJ

AF:

0.143

Gnomad4 EAS

AF:

0.645

Gnomad4 SAS

AF:

0.248

Gnomad4 FIN

AF:

0.0941

Gnomad4 NFE

AF:

0.129

Gnomad4 OTH

AF:

0.168

Alfa

AF:

0.142

Hom.:

3639

Bravo

AF:

0.185

Asia WGS

AF:

0.411

AC:

1426

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jan 07, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 42% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 39. Only high quality variants are reported. -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

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

-0.84

CADD

Benign

2.0

DANN

Benign

0.74

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