NM_001127222.2:c.7426T>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001127222.2(CACNA1A):c.7426T>G(p.Tyr2476Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,382,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y2476H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.54

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:

ENSG00000300728 (HGNC:):

ENSG00000300728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.7426T>G	p.Tyr2476Asp	missense_variant	Exon 47 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.7426T>G	p.Tyr2476Asp	missense_variant	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.7444T>G	p.Tyr2482Asp	missense_variant	Exon 48 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.7432T>G	p.Tyr2478Asp	missense_variant	Exon 47 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.7429T>G	p.Tyr2477Asp	missense_variant	Exon 47 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.7429T>G	p.Tyr2477Asp	missense_variant	Exon 47 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.7393T>G	p.Tyr2465Asp	missense_variant	Exon 46 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.7288T>G	p.Tyr2430Asp	missense_variant	Exon 46 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636768.2 link	n.*1687T>G		non_coding_transcript_exon_variant	Exon 45 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.*2605T>G		non_coding_transcript_exon_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636389.1 link	c.*512T>G		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.*638T>G		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000635895.1 link	c.*638T>G		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.*638T>G		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000636768.2 link	n.*1687T>G		3_prime_UTR_variant	Exon 45 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.*2605T>G		3_prime_UTR_variant	Exon 47 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000724

AC:

AN:

138216

AF XY:

0.0000131

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000184

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000434

AC:

AN:

1382924

Hom.:

Cov.:

AF XY:

0.00000877

AC XY:

AN XY:

684240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30744

American (AMR)

AF:

0.00

AC:

AN:

36242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24716

East Asian (EAS)

AF:

0.00

AC:

AN:

35350

South Asian (SAS)

AF:

0.00

AC:

AN:

79936

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5632

European-Non Finnish (NFE)

AF:

0.00000556

AC:

AN:

1078270

Other (OTH)

AF:

0.00

AC:

AN:

57438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 08, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CACNA1A c.*638T>G is located in the untranslated mRNA region downstream of the termination codon. In a different transcript this variant corresponds to a missense change (NM_001127222.2: c.7426T>G (p.Tyr2476Asp)). The variant allele was found at a frequency of 3.9e-06 in 1527368 control chromosomes in the gnomAD database (v4.1 dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.*638T>G in individuals affected with Epileptic Encephalopathy, Early Infantile, 42 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Uncertain

0.67

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

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.76

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

M_CAP

Pathogenic

0.98

MetaRNN

Uncertain

0.45

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

MetaSVM

Uncertain

0.46

PhyloP100

1.5

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-5.8

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

REVEL

Uncertain

0.41

Sift

Uncertain

0.0060

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

Sift4G

Uncertain

0.0080

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

Vest4

0.31

MutPred

0.27

.;Loss of phosphorylation at Y2476 (P = 0.0175);.;.;.;.;.;.;.;.;

MVP

0.88

MPC

1.0

ClinPred

0.65

GERP RS

2.9

Varity_R

0.44

gMVP

0.54

Mutation Taster

=82/18

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over