rs750826355

Variant names:

• chr19-13285142-TTCC-T
• rs750826355
• NM_001127222.2:c.3615_3617delGGA

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001127222.2(CACNA1A):​c.3615_3617delGGA​(p.Glu1206del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000031 in 1,613,894 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 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 3.87

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.

• BS2: High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3615_3617delGGA	p.Glu1206del	disruptive_inframe_deletion	Exon 21 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3615_3617delGGA	p.Glu1206del	disruptive_inframe_deletion	Exon 21 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3627_3629delGGA	p.Glu1210del	disruptive_inframe_deletion	Exon 21 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3621_3623delGGA	p.Glu1208del	disruptive_inframe_deletion	Exon 21 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3618_3620delGGA	p.Glu1207del	disruptive_inframe_deletion	Exon 21 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3618_3620delGGA	p.Glu1207del	disruptive_inframe_deletion	Exon 21 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3618_3620delGGA	p.Glu1207del	disruptive_inframe_deletion	Exon 21 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3477_3479delGGA	p.Glu1160del	disruptive_inframe_deletion	Exon 20 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3618_3620delGGA	p.Glu1207del	disruptive_inframe_deletion	Exon 21 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3627_3629delGGA	p.Glu1210del	disruptive_inframe_deletion	Exon 21 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3618_3620delGGA	p.Glu1207del	disruptive_inframe_deletion	Exon 21 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3621_3623delGGA	p.Glu1208del	disruptive_inframe_deletion	Exon 21 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3618_3620delGGA	p.Glu1207del	disruptive_inframe_deletion	Exon 21 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3618_3620delGGA	p.Glu1207del	disruptive_inframe_deletion	Exon 21 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3618_3620delGGA	p.Glu1207del	disruptive_inframe_deletion	Exon 21 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152104 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000446 AC: 11 AN: 246848 Hom.: 0 AF XY: 0.0000447 AC XY: 6 AN XY: 134136

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000723

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461672 Hom.: 0 AF XY: 0.0000248 AC XY: 18 AN XY: 727122

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152222 Hom.: 0 Cov.: 31 AF XY: 0.0000806 AC XY: 6 AN XY: 74422

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000642

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

May 14, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the CACNA1A gene. The c.3618_3620delGGA variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3618_3620delGGA variant is observed in 4/24,000 (0.02%) alleles from individuals of African background (Lek et al., 2016). The c.3618_3620delGGA variant results in an in-frame deletion of a single Glutamic acid residue, denoted p.Glu1207del. However, this deletion occurs at a position that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Feb 27, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Nov 20, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CACNA1A c.3618_3620delGGA (p.Glu1207del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 4.5e-05 in 246848 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CACNA1A causing Epileptic Encephalopathy, Early Infantile, 42, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3618_3620delGGA in individuals affected with Epileptic Encephalopathy, Early Infantile, 42 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 195574). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.3618_3620del, results in the deletion of 1 amino acid(s) of the CACNA1A protein (p.Glu1207del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs750826355, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 195574). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Developmental and epileptic encephalopathy, 42 Uncertain:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jul 24, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs750826355; hg19: chr19-13395956;