NM_001127222.2:c.4034G>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_001127222.2(CACNA1A):c.4034G>T(p.Arg1345Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1345Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.88

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001127222.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-13262789-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 19-13262789-C-A is Pathogenic according to our data. Variant chr19-13262789-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1803511.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.4034G>T	p.Arg1345Leu	missense_variant	Exon 25 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.4037G>T	p.Arg1346Leu	missense_variant	Exon 25 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.4034G>T	p.Arg1345Leu	missense_variant	Exon 25 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.4037G>T	p.Arg1346Leu	missense_variant	Exon 25 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.4046G>T	p.Arg1349Leu	missense_variant	Exon 25 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.4040G>T	p.Arg1347Leu	missense_variant	Exon 25 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.4037G>T	p.Arg1346Leu	missense_variant	Exon 25 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.4037G>T	p.Arg1346Leu	missense_variant	Exon 25 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.4037G>T	p.Arg1346Leu	missense_variant	Exon 25 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.3896G>T	p.Arg1299Leu	missense_variant	Exon 24 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.4037G>T	p.Arg1346Leu	missense_variant	Exon 25 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.4046G>T	p.Arg1349Leu	missense_variant	Exon 25 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.4037G>T	p.Arg1346Leu	missense_variant	Exon 25 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.4040G>T	p.Arg1347Leu	missense_variant	Exon 25 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.4037G>T	p.Arg1346Leu	missense_variant	Exon 25 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.4037G>T	p.Arg1346Leu	missense_variant	Exon 25 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.4037G>T		non_coding_transcript_exon_variant	Exon 25 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.4034G>T		non_coding_transcript_exon_variant	Exon 25 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Dec 07, 2022

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (gnomAD); 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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

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

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.7

.;.;.;.;H;.;.;.;.;.;.;.;H;.;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-6.9

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

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Vest4

0.95

MutPred

0.87

.;.;Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);.;Loss of MoRF binding (P = 0.0329);.;.;Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);.;Loss of MoRF binding (P = 0.0329);.;Loss of MoRF binding (P = 0.0329);

MVP

0.99

MPC

2.6

ClinPred

1.0

GERP RS

5.4

Varity_R

0.85

gMVP

1.0

Mutation Taster

=6/94

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over