NM_001127222.2:c.5897G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_001127222.2(CACNA1A):c.5897G>A(p.Arg1966Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000289 in 1,612,096 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 3.90

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 -8 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=0.015164733).

BP6

Variant 19-13214276-C-T is Benign according to our data. Variant chr19-13214276-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 381583.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=5, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.5897G>A	p.Arg1966Gln	missense_variant	Exon 40 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.5897G>A	p.Arg1966Gln	missense_variant	Exon 40 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.5915G>A	p.Arg1972Gln	missense_variant	Exon 41 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.5903G>A	p.Arg1968Gln	missense_variant	Exon 40 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.5900G>A	p.Arg1967Gln	missense_variant	Exon 40 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.5900G>A	p.Arg1967Gln	missense_variant	Exon 40 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.5900G>A	p.Arg1967Gln	missense_variant	Exon 40 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.5759G>A	p.Arg1920Gln	missense_variant	Exon 39 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.5900G>A	p.Arg1967Gln	missense_variant	Exon 40 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.5915G>A	p.Arg1972Gln	missense_variant	Exon 41 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.5906G>A	p.Arg1969Gln	missense_variant	Exon 41 of 48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.5903G>A	p.Arg1968Gln	missense_variant	Exon 40 of 47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.5900G>A	p.Arg1967Gln	missense_variant	Exon 40 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.5900G>A	p.Arg1967Gln	missense_variant	Exon 40 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.5900G>A	p.Arg1967Gln	missense_variant	Exon 40 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.1 link	n.*199G>A		non_coding_transcript_exon_variant	Exon 5 of 10	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000636768.1 link	n.*199G>A		3_prime_UTR_variant	Exon 5 of 10	5		ENSP00000490190.2	A0A1B0GUP3

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000594

AC:

147

AN:

247600

Hom.:

AF XY:

0.000609

AC XY:

AN XY:

134586

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.0108

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.000828

GnomAD4 exome

AF:

0.000277

AC:

405

AN:

1459762

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

197

AN XY:

726270

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.0103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000738

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.000400

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000708

Hom.:

Bravo

AF:

0.000442

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000230

AC:

ESP6500EA

AF:

0.000351

AC:

ExAC

AF:

0.000346

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Oct 31, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in ExAC with a MaxMAF of 0.06%. It is predicted to be pathogenic by predictive tools. It is not present in ClinVar. It has been seen in 1 patient with congenital hyperinsulinism and 1 with epilepsy. -

May 23, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Jun 03, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23869231, 21703448, 28488083) -

Jun 17, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Episodic ataxia type 2

Benign:1

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 21, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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

Pathogenic

0.67

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.13

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

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.015

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

MetaSVM

Uncertain

0.24

MutationAssessor

Uncertain

2.1

.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.8

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.73

Sift

Benign

0.079

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

Sift4G

Benign

0.061

T;T;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.81

MVP

0.89

MPC

0.55

ClinPred

0.14

GERP RS

4.7

Varity_R

0.57

gMVP

0.95

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