rs16027

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001127222.2(CACNA1A):c.3310G>A(p.Gly1104Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,606,038 control chromosomes in the GnomAD database, including 9,572 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.083 ( 662 hom., cov: 30)

Exomes 𝑓: 0.10 ( 8910 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 0.0340

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 -19 ACMG points.

PP2

Missense variant in the CACNA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. Gene score misZ: 5.7845 (above the threshold of 3.09). Trascript score misZ: 3.9354 (above the threshold of 3.09). GenCC associations: The gene is linked to benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.004124522).

BP6

Variant 19-13286746-C-T is Benign according to our data. Variant chr19-13286746-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 68428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13286746-C-T is described in Lovd as [Benign]. Variant chr19-13286746-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.3310G>A	p.Gly1104Ser	missense_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.3310G>A	p.Gly1104Ser	missense_variant	Exon 20 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.3322G>A	p.Gly1108Ser	missense_variant	Exon 20 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.3316G>A	p.Gly1106Ser	missense_variant	Exon 20 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.3313G>A	p.Gly1105Ser	missense_variant	Exon 20 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.3313G>A	p.Gly1105Ser	missense_variant	Exon 20 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.3313G>A	p.Gly1105Ser	missense_variant	Exon 20 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.3172G>A	p.Gly1058Ser	missense_variant	Exon 19 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.3313G>A	p.Gly1105Ser	missense_variant	Exon 20 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.3322G>A	p.Gly1108Ser	missense_variant	Exon 20 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.3313G>A	p.Gly1105Ser	missense_variant	Exon 20 of 48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.3316G>A	p.Gly1106Ser	missense_variant	Exon 20 of 47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.3313G>A	p.Gly1105Ser	missense_variant	Exon 20 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.3313G>A	p.Gly1105Ser	missense_variant	Exon 20 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.3313G>A	p.Gly1105Ser	missense_variant	Exon 20 of 46	5		ENSP00000489777.1	O00555-5

Frequencies

GnomAD3 genomes

AF:

0.0828

AC:

12562

AN:

151726

Hom.:

665

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0315

Gnomad AMI

AF:

0.0857

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.0740

Gnomad SAS

AF:

0.228

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0951

Gnomad OTH

AF:

0.0820

GnomAD3 exomes

AF:

0.109

AC:

25976

AN:

238848

Hom.:

1737

AF XY:

0.117

AC XY:

15279

AN XY:

130406

show subpopulations

Gnomad AFR exome

AF:

0.0294

Gnomad AMR exome

AF:

0.0915

Gnomad ASJ exome

AF:

0.105

Gnomad EAS exome

AF:

0.0852

Gnomad SAS exome

AF:

0.237

Gnomad FIN exome

AF:

0.0954

Gnomad NFE exome

AF:

0.0964

Gnomad OTH exome

AF:

0.0963

GnomAD4 exome

AF:

0.103

AC:

149879

AN:

1454194

Hom.:

8910

Cov.:

AF XY:

0.108

AC XY:

78130

AN XY:

722788

show subpopulations

Gnomad4 AFR exome

AF:

0.0300

Gnomad4 AMR exome

AF:

0.0890

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.0572

Gnomad4 SAS exome

AF:

0.236

Gnomad4 FIN exome

AF:

0.0890

Gnomad4 NFE exome

AF:

0.0977

Gnomad4 OTH exome

AF:

0.103

GnomAD4 genome

AF:

0.0826

AC:

12544

AN:

151844

Hom.:

662

Cov.:

AF XY:

0.0862

AC XY:

6394

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.0315

Gnomad4 AMR

AF:

0.103

Gnomad4 ASJ

AF:

0.111

Gnomad4 EAS

AF:

0.0735

Gnomad4 SAS

AF:

0.228

Gnomad4 FIN

AF:

0.103

Gnomad4 NFE

AF:

0.0951

Gnomad4 OTH

AF:

0.0802

Alfa

AF:

0.0971

Hom.:

1093

Bravo

AF:

0.0774

TwinsUK

AF:

0.0974

AC:

361

ALSPAC

AF:

0.0960

AC:

370

ESP6500AA

AF:

0.0331

AC:

128

ESP6500EA

AF:

0.0930

AC:

765

ExAC

AF:

0.107

AC:

12832

Asia WGS

AF:

0.116

AC:

408

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 05, 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. -

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 04, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

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. -

Aug 23, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

not provided

Benign:1Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

- -

Inborn genetic diseases

Benign:1

Mar 02, 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. -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42

Benign:1

Oct 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.69

DEOGEN2

Benign

0.019

.;.;T;.;.;.;.;.;.;T;.;.;.;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.83

T;T;T;T;T;T;T;T;.;T;T;T;T;T;T

MetaRNN

Benign

0.0041

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.1

.;.;.;.;L;.;.;.;.;.;.;.;L;.;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.0

.;N;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.17

Sift

Benign

0.19

.;T;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.19

T;T;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.050

MPC

0.086

ClinPred

0.012

GERP RS

-0.31

Varity_R

0.048

gMVP

0.44

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