19-13298941-C-T

Position:

chr19-13298941-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_001127222.2(CACNA1A):c.2692G>A(p.Gly898Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,592,736 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 4.75

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 Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.21210161).

BP6

Variant 19-13298941-C-T is Benign according to our data. Variant chr19-13298941-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 572781.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 linkuse as main transcript	c.2692G>A	p.Gly898Ser	missense_variant	19/47	ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000360228.11 linkuse as main transcript	c.2692G>A	p.Gly898Ser	missense_variant	19/47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 linkuse as main transcript	c.2704G>A	p.Gly902Ser	missense_variant	19/48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 linkuse as main transcript	c.2698G>A	p.Gly900Ser	missense_variant	19/47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 linkuse as main transcript	c.2695G>A	p.Gly899Ser	missense_variant	19/47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 linkuse as main transcript	c.2695G>A	p.Gly899Ser	missense_variant	19/47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 linkuse as main transcript	c.2695G>A	p.Gly899Ser	missense_variant	19/46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 linkuse as main transcript	c.2554G>A	p.Gly852Ser	missense_variant	18/46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 linkuse as main transcript	c.2695G>A	p.Gly899Ser	missense_variant	19/47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 linkuse as main transcript	c.2704G>A	p.Gly902Ser	missense_variant	19/48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 linkuse as main transcript	c.2695G>A	p.Gly899Ser	missense_variant	19/48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 linkuse as main transcript	c.2698G>A	p.Gly900Ser	missense_variant	19/47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 linkuse as main transcript	c.2695G>A	p.Gly899Ser	missense_variant	19/47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 linkuse as main transcript	c.2695G>A	p.Gly899Ser	missense_variant	19/47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 linkuse as main transcript	c.2695G>A	p.Gly899Ser	missense_variant	19/46	5		ENSP00000489777.1	O00555-5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000372

AC:

AN:

214956

Hom.:

AF XY:

0.0000418

AC XY:

AN XY:

119734

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000410

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000118

AC:

170

AN:

1440550

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

716688

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000908

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000140

Gnomad4 OTH exome

AF:

0.000167

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000583

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.00000852

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Migraine, familial hemiplegic, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jul 18, 2022

_x000D_ Criteria applied: PP3, BS1 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 09, 2024

Variant summary: CACNA1A c.2695G>A (p.Gly899Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was detected at a frequency of 0.00011 in 1592736 control chromosomes, suggesting the variant could be benign. To our knowledge, no occurrence of c.2695G>A in individuals affected with Epileptic Encephalopathy, Early Infantile, 42 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 572781). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2019

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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 29, 2020

- -

CACNA1A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0083

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

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.87

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

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.21

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

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

1.5

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

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.28

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

REVEL

Uncertain

0.32

Sift

Benign

0.41

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

Sift4G

Benign

0.57

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

Vest4

0.11

MutPred

0.16

.;.;Gain of phosphorylation at G899 (P = 0.0057);Gain of phosphorylation at G899 (P = 0.0057);Gain of phosphorylation at G899 (P = 0.0057);.;Gain of phosphorylation at G899 (P = 0.0057);.;.;Gain of phosphorylation at G899 (P = 0.0057);Gain of phosphorylation at G899 (P = 0.0057);.;Gain of phosphorylation at G899 (P = 0.0057);.;Gain of phosphorylation at G899 (P = 0.0057);

MVP

0.94

MPC

1.1

ClinPred

0.13

GERP RS

3.0

Varity_R

0.071

gMVP

0.52

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