19-13298882-C-G

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.2751G>C(p.Glu917Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,592,562 control chromosomes in the GnomAD database, including 15,785 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E917E) has been classified as Benign.

Frequency

Genomes: 𝑓 0.12 ( 1247 hom., cov: 32)

Exomes 𝑓: 0.14 ( 14538 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 0.00200

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=0.0017104447).

BP6

Variant 19-13298882-C-G is Benign according to our data. Variant chr19-13298882-C-G is described in ClinVar as [Benign]. Clinvar id is 68426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298882-C-G is described in Lovd as [Benign]. Variant chr19-13298882-C-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.2751G>C	p.Glu917Asp	missense_variant	Exon 19 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.2751G>C	p.Glu917Asp	missense_variant	Exon 19 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.2763G>C	p.Glu921Asp	missense_variant	Exon 19 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.2757G>C	p.Glu919Asp	missense_variant	Exon 19 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.2754G>C	p.Glu918Asp	missense_variant	Exon 19 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.2754G>C	p.Glu918Asp	missense_variant	Exon 19 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.2754G>C	p.Glu918Asp	missense_variant	Exon 19 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.2613G>C	p.Glu871Asp	missense_variant	Exon 18 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.2754G>C	p.Glu918Asp	missense_variant	Exon 19 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.2763G>C	p.Glu921Asp	missense_variant	Exon 19 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.2754G>C	p.Glu918Asp	missense_variant	Exon 19 of 48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.2757G>C	p.Glu919Asp	missense_variant	Exon 19 of 47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.2754G>C	p.Glu918Asp	missense_variant	Exon 19 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.2754G>C	p.Glu918Asp	missense_variant	Exon 19 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.2754G>C	p.Glu918Asp	missense_variant	Exon 19 of 46	5		ENSP00000489777.1	O00555-5

Frequencies

GnomAD3 genomes

AF:

0.122

AC:

18593

AN:

152102

Hom.:

1247

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0721

Gnomad AMI

AF:

0.162

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.154

Gnomad EAS

AF:

0.123

Gnomad SAS

AF:

0.120

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.162

Gnomad NFE

AF:

0.147

Gnomad OTH

AF:

0.140

GnomAD3 exomes

AF:

0.126

AC:

27267

AN:

215748

Hom.:

1777

AF XY:

0.125

AC XY:

15073

AN XY:

120314

show subpopulations

Gnomad AFR exome

AF:

0.0630

Gnomad AMR exome

AF:

0.137

Gnomad ASJ exome

AF:

0.151

Gnomad EAS exome

AF:

0.0982

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.112

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.139

GnomAD4 exome

AF:

0.140

AC:

201088

AN:

1440352

Hom.:

14538

Cov.:

AF XY:

0.139

AC XY:

99703

AN XY:

716648

show subpopulations

Gnomad4 AFR exome

AF:

0.0667

Gnomad4 AMR exome

AF:

0.141

Gnomad4 ASJ exome

AF:

0.153

Gnomad4 EAS exome

AF:

0.142

Gnomad4 SAS exome

AF:

0.115

Gnomad4 FIN exome

AF:

0.120

Gnomad4 NFE exome

AF:

0.144

Gnomad4 OTH exome

AF:

0.143

GnomAD4 genome

AF:

0.122

AC:

18601

AN:

152210

Hom.:

1247

Cov.:

AF XY:

0.121

AC XY:

9005

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0722

Gnomad4 AMR

AF:

0.136

Gnomad4 ASJ

AF:

0.154

Gnomad4 EAS

AF:

0.122

Gnomad4 SAS

AF:

0.120

Gnomad4 FIN

AF:

0.123

Gnomad4 NFE

AF:

0.147

Gnomad4 OTH

AF:

0.139

Alfa

AF:

0.0877

Hom.:

185

Bravo

AF:

0.121

TwinsUK

AF:

0.135

AC:

501

ALSPAC

AF:

0.141

AC:

545

ESP6500AA

AF:

0.0585

AC:

206

ESP6500EA

AF:

0.116

AC:

883

ExAC

AF:

0.119

AC:

13837

Asia WGS

AF:

0.115

AC:

397

AN:

3462

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

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 30% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 28. Only high quality variants are reported. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

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. -

May 03, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2014

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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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 16, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.58

DEOGEN2

Benign

0.024

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

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.59

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

MetaRNN

Benign

0.0017

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

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.90

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

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.66

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

REVEL

Benign

0.25

Sift

Benign

0.43

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

Sift4G

Benign

0.11

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

Vest4

0.013

MutPred

0.17

.;.;Gain of MoRF binding (P = 0.2255);Gain of MoRF binding (P = 0.2255);Gain of MoRF binding (P = 0.2255);.;Gain of MoRF binding (P = 0.2255);.;.;Gain of MoRF binding (P = 0.2255);Gain of MoRF binding (P = 0.2255);.;Gain of MoRF binding (P = 0.2255);.;Gain of MoRF binding (P = 0.2255);

MPC

2.0

ClinPred

0.0072

GERP RS

1.5

Varity_R

0.045

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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