19-13208879-ATGGTGGTGGTGGTGGTGG-ATGGTGG

Variant names:

• chr19-13208879-ATGGTGGTGGTGG-A
• rs759331923
• NM_001127222.2:c.6645_6656delCCACCACCACCA

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_001127222.2(CACNA1A):​c.6645_6656delCCACCACCACCA​(p.His2216_His2219del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000454 in 1,454,150 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 8.26

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 -4 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 19-13208879-ATGGTGGTGGTGG-A is Benign according to our data. Variant chr19-13208879-ATGGTGGTGGTGG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421291.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6645_6656delCCACCACCACCA	p.His2216_His2219del	disruptive_inframe_deletion	Exon 46 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6645_6656delCCACCACCACCA	p.His2216_His2219del	disruptive_inframe_deletion	Exon 46 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6663_6674delCCACCACCACCA	p.His2222_His2225del	disruptive_inframe_deletion	Exon 47 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6651_6662delCCACCACCACCA	p.His2218_His2221del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6648_6659delCCACCACCACCA	p.His2217_His2220del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6648_6659delCCACCACCACCA	p.His2217_His2220del	disruptive_inframe_deletion	Exon 46 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6612_6623delCCACCACCACCA	p.His2205_His2208del	disruptive_inframe_deletion	Exon 45 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6507_6518delCCACCACCACCA	p.His2170_His2173del	disruptive_inframe_deletion	Exon 45 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6648_6659delCCACCACCACCA	p.His2217_His2220del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6663_6674delCCACCACCACCA	p.His2222_His2225del	disruptive_inframe_deletion	Exon 47 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6654_6665delCCACCACCACCA	p.His2219_His2222del	disruptive_inframe_deletion	Exon 47 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6651_6662delCCACCACCACCA	p.His2218_His2221del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6648_6659delCCACCACCACCA	p.His2217_His2220del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6648_6659delCCACCACCACCA	p.His2217_His2220del	disruptive_inframe_deletion	Exon 46 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6612_6623delCCACCACCACCA	p.His2205_His2208del	disruptive_inframe_deletion	Exon 45 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*911_*922delCCACCACCACCA		downstream_gene_variant		5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.0000336 AC: 5 AN: 148640 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000246

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: 0.0000598

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000467 AC: 61 AN: 1305510 Hom.: 0 AF XY: 0.0000356 AC XY: 23 AN XY: 645420

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000584

Gnomad4 SAS exome AF: 0.0000130

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000552

Gnomad4 OTH exome AF: 0.0000368

GnomAD4 genome AF: 0.0000336 AC: 5 AN: 148640 Hom.: 0 Cov.: 31 AF XY: 0.0000276 AC XY: 2 AN XY: 72384

Gnomad4 AFR AF: 0.0000246

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: 0.0000598

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 1 Uncertain:1

Apr 27, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tip-toe gait Uncertain:1

Jan 29, 2021

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

not provided Benign:1

Feb 10, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs759331923; hg19: chr19-13319693;