19-13285153-CCTT-CCTTCTT

Position:

• chr19-13285153-CCTT-CCTTCTT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001127222.2(CACNA1A):​c.3604_3606dupAAG​(p.Lys1202dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.398

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3604_3606dupAAG	p.Lys1202dup	conservative_inframe_insertion	21/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3604_3606dupAAG	p.Lys1202dup	conservative_inframe_insertion	21/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3616_3618dupAAG	p.Lys1206dup	conservative_inframe_insertion	21/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3610_3612dupAAG	p.Lys1204dup	conservative_inframe_insertion	21/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3607_3609dupAAG	p.Lys1203dup	conservative_inframe_insertion	21/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3607_3609dupAAG	p.Lys1203dup	conservative_inframe_insertion	21/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3607_3609dupAAG	p.Lys1203dup	conservative_inframe_insertion	21/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3466_3468dupAAG	p.Lys1156dup	conservative_inframe_insertion	20/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3607_3609dupAAG	p.Lys1203dup	conservative_inframe_insertion	21/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3616_3618dupAAG	p.Lys1206dup	conservative_inframe_insertion	21/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3607_3609dupAAG	p.Lys1203dup	conservative_inframe_insertion	21/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3610_3612dupAAG	p.Lys1204dup	conservative_inframe_insertion	21/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3607_3609dupAAG	p.Lys1203dup	conservative_inframe_insertion	21/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3607_3609dupAAG	p.Lys1203dup	conservative_inframe_insertion	21/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3607_3609dupAAG	p.Lys1203dup	conservative_inframe_insertion	21/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246840 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461684 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs772989979; hg19: chr19-13395967;