rs1555756483

Variant names:

• chr19-13299358-A-G
• rs1555756483
• NM_001127222.2:c.2280-5T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-13299358-A-G
• chr19-13299358-A-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001127222.2(CACNA1A):​c.2280-5T>C variant causes a splice region, intron 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. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 splice_region, intron
• Scores: Splicing: ADA: 0.0005953
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.65
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2280-5T>C		splice_region_variant, intron_variant	Intron 18 of 46	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2280-5T>C		splice_region_variant, intron_variant	Intron 18 of 46	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2292-5T>C		splice_region_variant, intron_variant	Intron 18 of 47	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2286-5T>C		splice_region_variant, intron_variant	Intron 18 of 46	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2283-5T>C		splice_region_variant, intron_variant	Intron 18 of 46	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2283-5T>C		splice_region_variant, intron_variant	Intron 18 of 46	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2283-5T>C		splice_region_variant, intron_variant	Intron 18 of 45	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2142-5T>C		splice_region_variant, intron_variant	Intron 17 of 45	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2283-5T>C		splice_region_variant, intron_variant	Intron 18 of 46	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2292-5T>C		splice_region_variant, intron_variant	Intron 18 of 47	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2283-5T>C		splice_region_variant, intron_variant	Intron 18 of 47	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2286-5T>C		splice_region_variant, intron_variant	Intron 18 of 46	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2283-5T>C		splice_region_variant, intron_variant	Intron 18 of 46	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2283-5T>C		splice_region_variant, intron_variant	Intron 18 of 46	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2283-5T>C		splice_region_variant, intron_variant	Intron 18 of 45	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.2283-5T>C		splice_region_variant, intron_variant	Intron 18 of 44	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.2280-5T>C		splice_region_variant, intron_variant	Intron 18 of 46			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.4
DANN	Benign	0.48
PhyloP100		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00060
dbscSNV1_RF	Benign	0.040
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

Other links and lift over

dbSNP: rs1555756483; hg19: chr19-13410172;