19-13207408-A-C

Variant names:

• chr19-13207408-A-C
• rs779631503
• NM_001127222.2:c.7426T>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in the CACNA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. Gene score misZ: 5.7845 (above the threshold of 3.09). Trascript score misZ: 3.9354 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• 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	c.7426T>G	p.Tyr2476Asp	missense_variant	Exon 47 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.7426T>G	p.Tyr2476Asp	missense_variant	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.7444T>G	p.Tyr2482Asp	missense_variant	Exon 48 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.7432T>G	p.Tyr2478Asp	missense_variant	Exon 47 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.7429T>G	p.Tyr2477Asp	missense_variant	Exon 47 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.7429T>G	p.Tyr2477Asp	missense_variant	Exon 47 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.7393T>G	p.Tyr2465Asp	missense_variant	Exon 46 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.7288T>G	p.Tyr2430Asp	missense_variant	Exon 46 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389	c.*512T>G		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432	c.*638T>G		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000635895	c.*638T>G		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009	c.*638T>G		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000724 AC: 1 AN: 138216 Hom.: 0 AF XY: 0.0000131 AC XY: 1 AN XY: 76536

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 SAS 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: 6 AN: 1382924 Hom.: 0 Cov.: 30 AF XY: 0.00000877 AC XY: 6 AN XY: 684240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000556

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
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	N
LIST_S2	Benign	0.76	T;T;T;T;T;T;.;T;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.46	D
PrimateAI	Pathogenic	0.95	D
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	D
GERP RS		2.9
Varity_R		0.44
gMVP		0.54

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

Other links and lift over

dbSNP: rs779631503; hg19: chr19-13318222;