NM_001127222.2:c.1267A>G

Variant names:

• chr19-13330322-T-C
• NM_001127222.2:c.1267A>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Strong BP6_Moderate

The NM_001127222.2(CACNA1A):​c.1267A>G​(p.Thr423Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.959

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.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.044733614).
• BP6: Variant 19-13330322-T-C is Benign according to our data. Variant chr19-13330322-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1765299.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	c.1267A>G	p.Thr423Ala	missense_variant	Exon 10 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1267A>G	p.Thr423Ala	missense_variant	Exon 10 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1270A>G	p.Thr424Ala	missense_variant	Exon 10 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1273A>G	p.Thr425Ala	missense_variant	Exon 10 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1270A>G	p.Thr424Ala	missense_variant	Exon 10 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1270A>G	p.Thr424Ala	missense_variant	Exon 10 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1270A>G	p.Thr424Ala	missense_variant	Exon 10 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1129A>G	p.Thr377Ala	missense_variant	Exon 9 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1270A>G	p.Thr424Ala	missense_variant	Exon 10 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1270A>G	p.Thr424Ala	missense_variant	Exon 10 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1270A>G	p.Thr424Ala	missense_variant	Exon 10 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1273A>G	p.Thr425Ala	missense_variant	Exon 10 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1270A>G	p.Thr424Ala	missense_variant	Exon 10 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1270A>G	p.Thr424Ala	missense_variant	Exon 10 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1270A>G	p.Thr424Ala	missense_variant	Exon 10 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Nov 16, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.046
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.71
DEOGEN2	Benign	0.0019	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.52	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.045	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	-0.93	.;.;.;.;N;.;.;N;.;.;.;.;N;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.83	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.32
Sift	Benign	1.0	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	1.0	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.048
MutPred		0.28		Loss of phosphorylation at T424 (P = 0.0751);.;Loss of phosphorylation at T424 (P = 0.0751);Loss of phosphorylation at T424 (P = 0.0751);Loss of phosphorylation at T424 (P = 0.0751);.;Loss of phosphorylation at T424 (P = 0.0751);Loss of phosphorylation at T424 (P = 0.0751);Loss of phosphorylation at T424 (P = 0.0751);Loss of phosphorylation at T424 (P = 0.0751);Loss of phosphorylation at T424 (P = 0.0751);.;Loss of phosphorylation at T424 (P = 0.0751);.;Loss of phosphorylation at T424 (P = 0.0751);
MVP		0.50
MPC		1.1
ClinPred		0.023	T
GERP RS		0.99
Varity_R		0.030
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-13441136;