rs16029

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001127222.2(CACNA1A):c.3546C>T(p.Val1182Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,368,834 control chromosomes in the GnomAD database, including 341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 36 hom., cov: 30)

Exomes 𝑓: 0.020 ( 305 hom. )

Consequence

CACNA1A
NM_001127222.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.594

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 19-13286510-G-A is Benign according to our data. Variant chr19-13286510-G-A is described in ClinVar as [Benign]. Clinvar id is 93561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13286510-G-A is described in Lovd as [Benign]. Variant chr19-13286510-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.594 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0173 (2612/151270) while in subpopulation NFE AF= 0.0274 (1857/67692). AF 95% confidence interval is 0.0264. There are 36 homozygotes in gnomad4. There are 1274 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2612 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.3546C>T	p.Val1182Val	synonymous_variant	Exon 20 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.3546C>T	p.Val1182Val	synonymous_variant	Exon 20 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.3558C>T	p.Val1186Val	synonymous_variant	Exon 20 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.3552C>T	p.Val1184Val	synonymous_variant	Exon 20 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.3549C>T	p.Val1183Val	synonymous_variant	Exon 20 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.3549C>T	p.Val1183Val	synonymous_variant	Exon 20 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.3549C>T	p.Val1183Val	synonymous_variant	Exon 20 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.3408C>T	p.Val1136Val	synonymous_variant	Exon 19 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.3549C>T	p.Val1183Val	synonymous_variant	Exon 20 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.3558C>T	p.Val1186Val	synonymous_variant	Exon 20 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.3549C>T	p.Val1183Val	synonymous_variant	Exon 20 of 48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.3552C>T	p.Val1184Val	synonymous_variant	Exon 20 of 47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.3549C>T	p.Val1183Val	synonymous_variant	Exon 20 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.3549C>T	p.Val1183Val	synonymous_variant	Exon 20 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.3549C>T	p.Val1183Val	synonymous_variant	Exon 20 of 46	5		ENSP00000489777.1	O00555-5

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2611

AN:

151146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00373

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.00998

Gnomad ASJ

AF:

0.0188

Gnomad EAS

AF:

0.000392

Gnomad SAS

AF:

0.0147

Gnomad FIN

AF:

0.0244

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0274

Gnomad OTH

AF:

0.0154

GnomAD3 exomes

AF:

0.0170

AC:

2890

AN:

169562

Hom.:

AF XY:

0.0178

AC XY:

1599

AN XY:

89896

show subpopulations

Gnomad AFR exome

AF:

0.00417

Gnomad AMR exome

AF:

0.00916

Gnomad ASJ exome

AF:

0.0156

Gnomad EAS exome

AF:

0.000134

Gnomad SAS exome

AF:

0.0109

Gnomad FIN exome

AF:

0.0256

Gnomad NFE exome

AF:

0.0234

Gnomad OTH exome

AF:

0.0212

GnomAD4 exome

AF:

0.0196

AC:

23841

AN:

1217564

Hom.:

305

Cov.:

AF XY:

0.0197

AC XY:

11884

AN XY:

603788

show subpopulations

Gnomad4 AFR exome

AF:

0.00323

Gnomad4 AMR exome

AF:

0.0103

Gnomad4 ASJ exome

AF:

0.0146

Gnomad4 EAS exome

AF:

0.000135

Gnomad4 SAS exome

AF:

0.0126

Gnomad4 FIN exome

AF:

0.0276

Gnomad4 NFE exome

AF:

0.0214

Gnomad4 OTH exome

AF:

0.0180

GnomAD4 genome

AF:

0.0173

AC:

2612

AN:

151270

Hom.:

Cov.:

AF XY:

0.0172

AC XY:

1274

AN XY:

73914

show subpopulations

Gnomad4 AFR

AF:

0.00372

Gnomad4 AMR

AF:

0.00997

Gnomad4 ASJ

AF:

0.0188

Gnomad4 EAS

AF:

0.000392

Gnomad4 SAS

AF:

0.0149

Gnomad4 FIN

AF:

0.0244

Gnomad4 NFE

AF:

0.0274

Gnomad4 OTH

AF:

0.0152

Alfa

AF:

0.0221

Hom.:

Bravo

AF:

0.0143

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Jun 24, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 12, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 19, 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. -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 15, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

-0.45

CADD

Benign

1.3

DANN

Benign

0.69

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