Variant 19-13298647-GGCCCTCGCCCTC-GGCCCTCGCCCTCGCCCTCGCCCTC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4

The NM_001127222.2(CACNA1A):c.2974_2985dupGAGGGCGAGGGC(p.Gly995_Pro996insGluGlyGluGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000033 in 1,517,336 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.91

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001127222.2.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 linkuse as main transcript	c.2974_2985dupGAGGGCGAGGGC	p.Gly995_Pro996insGluGlyGluGly	conservative_inframe_insertion	19/47	ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000360228.11 linkuse as main transcript	c.2974_2985dupGAGGGCGAGGGC	p.Gly995_Pro996insGluGlyGluGly	conservative_inframe_insertion	19/47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 linkuse as main transcript	c.2986_2997dupGAGGGCGAGGGC	p.Gly999_Pro1000insGluGlyGluGly	conservative_inframe_insertion	19/48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 linkuse as main transcript	c.2980_2991dupGAGGGCGAGGGC	p.Gly997_Pro998insGluGlyGluGly	conservative_inframe_insertion	19/47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 linkuse as main transcript	c.2977_2988dupGAGGGCGAGGGC	p.Gly996_Pro997insGluGlyGluGly	conservative_inframe_insertion	19/47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 linkuse as main transcript	c.2977_2988dupGAGGGCGAGGGC	p.Gly996_Pro997insGluGlyGluGly	conservative_inframe_insertion	19/47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 linkuse as main transcript	c.2977_2988dupGAGGGCGAGGGC	p.Gly996_Pro997insGluGlyGluGly	conservative_inframe_insertion	19/46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 linkuse as main transcript	c.2836_2847dupGAGGGCGAGGGC	p.Gly949_Pro950insGluGlyGluGly	conservative_inframe_insertion	18/46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 linkuse as main transcript	c.2977_2988dupGAGGGCGAGGGC	p.Gly996_Pro997insGluGlyGluGly	conservative_inframe_insertion	19/47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 linkuse as main transcript	c.2986_2997dupGAGGGCGAGGGC	p.Gly999_Pro1000insGluGlyGluGly	conservative_inframe_insertion	19/48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 linkuse as main transcript	c.2977_2988dupGAGGGCGAGGGC	p.Gly996_Pro997insGluGlyGluGly	conservative_inframe_insertion	19/48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 linkuse as main transcript	c.2980_2991dupGAGGGCGAGGGC	p.Gly997_Pro998insGluGlyGluGly	conservative_inframe_insertion	19/47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 linkuse as main transcript	c.2977_2988dupGAGGGCGAGGGC	p.Gly996_Pro997insGluGlyGluGly	conservative_inframe_insertion	19/47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 linkuse as main transcript	c.2977_2988dupGAGGGCGAGGGC	p.Gly996_Pro997insGluGlyGluGly	conservative_inframe_insertion	19/47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 linkuse as main transcript	c.2977_2988dupGAGGGCGAGGGC	p.Gly996_Pro997insGluGlyGluGly	conservative_inframe_insertion	19/46	5		ENSP00000489777.1	O00555-5

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151922

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000875

AC:

AN:

114332

Hom.:

AF XY:

0.0000160

AC XY:

AN XY:

62386

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000243

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000293

AC:

AN:

1365414

Hom.:

Cov.:

AF XY:

0.00000446

AC XY:

AN XY:

673334

show subpopulations

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:

0.00000376

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151922

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74186

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over