rs563345694

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2

The NM_001127222.2(CACNA1A):c.6125C>T(p.Thr2042Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000639 in 1,610,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T2042T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 7.59

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:

CACNA1A (HGNC:):

CACNA1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 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.

BP6

Variant 19-13212448-G-A is Benign according to our data. Variant chr19-13212448-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 386521.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 linkuse as main transcript	c.6125C>T	p.Thr2042Met	missense_variant	42/47	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.6125C>T	p.Thr2042Met	missense_variant	42/47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 linkuse as main transcript	c.6143C>T	p.Thr2048Met	missense_variant	43/48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 linkuse as main transcript	c.6131C>T	p.Thr2044Met	missense_variant	42/47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 linkuse as main transcript	c.6128C>T	p.Thr2043Met	missense_variant	42/47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 linkuse as main transcript	c.6128C>T	p.Thr2043Met	missense_variant	42/47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 linkuse as main transcript	c.6128C>T	p.Thr2043Met	missense_variant	42/46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 linkuse as main transcript	c.5987C>T	p.Thr1996Met	missense_variant	41/46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 linkuse as main transcript	c.6128C>T	p.Thr2043Met	missense_variant	42/47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 linkuse as main transcript	c.6143C>T	p.Thr2048Met	missense_variant	43/48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 linkuse as main transcript	c.6134C>T	p.Thr2045Met	missense_variant	43/48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 linkuse as main transcript	c.6131C>T	p.Thr2044Met	missense_variant	42/47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 linkuse as main transcript	c.6128C>T	p.Thr2043Met	missense_variant	42/47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 linkuse as main transcript	c.6128C>T	p.Thr2043Met	missense_variant	42/47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 linkuse as main transcript	c.6128C>T	p.Thr2043Met	missense_variant	42/46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.1 linkuse as main transcript	n.*427C>T		non_coding_transcript_exon_variant	7/10	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000636768.1 linkuse as main transcript	n.*427C>T		3_prime_UTR_variant	7/10	5		ENSP00000490190.2	A0A1B0GUP3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000374

AC:

AN:

240506

Hom.:

AF XY:

0.0000460

AC XY:

AN XY:

130564

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000597

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:

0.0000548

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.0000651

AC:

AN:

1458688

Hom.:

Cov.:

AF XY:

0.0000607

AC XY:

AN XY:

725350

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000681

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000747

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000882

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30755392) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 27, 2018	- -

Neurogenic bladder;C0026826:Hypertonia;C0026838:Spasticity;C0026975:Myelitis;C0151786:Muscle weakness;C0151945:Cerebral venous thrombosis;C0231687:Spastic gait;C0948163:Abnormal cerebral white matter morphology;C1855710:Bone marrow hypocellularity;C2711630:Combined immunodeficiency;C4022749:Abnormal brainstem MRI signal intensity;C4022770:Abnormal thalamic MRI signal intensity

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

- -

CACNA1A-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 28, 2022

The CACNA1A c.6125C>T variant is predicted to result in the amino acid substitution p.Thr2042Met. This variant was reported in an individual with cerebral white matter abnormalities, cerebral venous thrombosis, myelitis, immunodeficiency, and spasticity (referred to as c.6128C>T, p.Thr2043Met in Supplemental Table 2, Ji et al. 2019. PubMed ID: 30755392). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-13323262-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

Jan 04, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

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

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.68

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.79

MutationAssessor

Uncertain

2.4

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

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.3

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

REVEL

Pathogenic

0.68

Sift

Uncertain

0.010

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

Sift4G

Benign

0.11

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

Vest4

0.51

MutPred

0.34

.;.;Loss of methylation at K2042 (P = 0.0508);Loss of methylation at K2042 (P = 0.0508);Loss of methylation at K2042 (P = 0.0508);.;.;Loss of methylation at K2042 (P = 0.0508);.;.;.;Loss of methylation at K2042 (P = 0.0508);Loss of methylation at K2042 (P = 0.0508);.;Loss of methylation at K2042 (P = 0.0508);.;.;.;

MVP

0.93

MPC

0.88

ClinPred

0.61

GERP RS

3.6

Varity_R

0.10

gMVP

0.34

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