NM_001127222.2:c.5740G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_001127222.2(CACNA1A):c.5740G>A(p.Asp1914Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,212 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1914G) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.06

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

episodic ataxia type 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
developmental and epileptic encephalopathy, 42
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
migraine, familial hemiplegic, 1
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
spinocerebellar ataxia type 6
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
benign paroxysmal torticollis of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial or sporadic hemiplegic migraine
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Lennox-Gastaut syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CACNA1A links:

ENSG00000300728 (HGNC:):

ENSG00000300728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.34954685).

BP6

Variant 19-13214600-C-T is Benign according to our data. Variant chr19-13214600-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 585577.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.5740G>A	p.Asp1914Asn	missense_variant	Exon 39 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.5740G>A	p.Asp1914Asn	missense_variant	Exon 39 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.5758G>A	p.Asp1920Asn	missense_variant	Exon 40 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.5746G>A	p.Asp1916Asn	missense_variant	Exon 39 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.5743G>A	p.Asp1915Asn	missense_variant	Exon 39 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.5743G>A	p.Asp1915Asn	missense_variant	Exon 39 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.5743G>A	p.Asp1915Asn	missense_variant	Exon 39 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.5602G>A	p.Asp1868Asn	missense_variant	Exon 38 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.5743G>A	p.Asp1915Asn	missense_variant	Exon 39 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.5758G>A	p.Asp1920Asn	missense_variant	Exon 40 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.5749G>A	p.Asp1917Asn	missense_variant	Exon 40 of 48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.5746G>A	p.Asp1916Asn	missense_variant	Exon 39 of 47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.5743G>A	p.Asp1915Asn	missense_variant	Exon 39 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.5743G>A	p.Asp1915Asn	missense_variant	Exon 39 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.5743G>A	p.Asp1915Asn	missense_variant	Exon 39 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.2 link	n.*42G>A		non_coding_transcript_exon_variant	Exon 38 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.*955G>A		non_coding_transcript_exon_variant	Exon 40 of 47			ENSP00000519091.1
CACNA1A	ENST00000636768.2 link	n.*42G>A		3_prime_UTR_variant	Exon 38 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.*955G>A		3_prime_UTR_variant	Exon 40 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000202

AC:

AN:

247780

AF XY:

0.00000744

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1460986

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726714

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.0000224

AC:

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000465

AC:

AN:

86090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111556

Other (OTH)

AF:

0.0000331

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41464

American (AMR)

AF:

0.000131

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000902

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.00000825

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 23, 2022

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) Computational tools disagree on the variant's effect on normal protein function. -

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

Benign:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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

Uncertain

0.55

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.064

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

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

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

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.35

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

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.77

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

PhyloP100

2.1

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.0

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

REVEL

Benign

0.22

Sift

Uncertain

0.0080

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

Sift4G

Uncertain

0.013

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

Vest4

0.49

MVP

0.81

MPC

2.2

ClinPred

0.53

GERP RS

4.7

Varity_R

0.21

gMVP

0.76

Mutation Taster

=50/50

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over