19-13208877-GGAT-GGATGAT

Position:

• chr19-13208877-GGAT-GGATGAT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM4_Supporting BP6 BS2

The NM_001127222.2(CACNA1A):​c.6656_6658dupATC​(p.His2219dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.0000199 in 1,459,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_insertion
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 5.98

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 Likely_benign. Variant got -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001127222.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 19-13208877-G-GGAT is Benign according to our data. Variant chr19-13208877-G-GGAT is described in ClinVar as [Likely_benign]. Clinvar id is 975350.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6656_6658dupATC	p.His2219dup	conservative_inframe_insertion	46/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6656_6658dupATC	p.His2219dup	conservative_inframe_insertion	46/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6674_6676dupATC	p.His2225dup	conservative_inframe_insertion	47/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6662_6664dupATC	p.His2221dup	conservative_inframe_insertion	46/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6659_6661dupATC	p.His2220dup	conservative_inframe_insertion	46/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6659_6661dupATC	p.His2220dup	conservative_inframe_insertion	46/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6623_6625dupATC	p.His2208dup	conservative_inframe_insertion	45/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6518_6520dupATC	p.His2173dup	conservative_inframe_insertion	45/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6659_6661dupATC	p.His2220dup	conservative_inframe_insertion	46/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6674_6676dupATC	p.His2225dup	conservative_inframe_insertion	47/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6665_6667dupATC	p.His2222dup	conservative_inframe_insertion	47/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6662_6664dupATC	p.His2221dup	conservative_inframe_insertion	46/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6659_6661dupATC	p.His2220dup	conservative_inframe_insertion	46/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6659_6661dupATC	p.His2220dup	conservative_inframe_insertion	46/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6623_6625dupATC	p.His2208dup	conservative_inframe_insertion	45/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150462 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 27 AN: 1309460 Hom.: 0 Cov.: 74 AF XY: 0.0000263 AC XY: 17 AN XY: 646842

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: 0.0000264

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150462 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73422

Gnomad4 AFR AF: 0.00

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: 0.0000296

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

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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: rs749638821; hg19: chr19-13319691;