1-181721870-GC-AT

Variant names:

• chr1-181721870-GC-AT
• NM_001205293.3:c.2069_2070delGCinsAT
• CACNA1E p.Gly690Asp

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM5 PP3

The NM_001205293.3(CACNA1E):​c.2069_2070delGCinsAT​(p.Gly690Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G690V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1E NM_001205293.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

Genes affected

CACNA1E (HGNC:1392): (calcium voltage-gated channel subunit alpha1 E) Voltage-dependent calcium channels are multisubunit complexes consisting of alpha-1, alpha-2, beta, and delta subunits in a 1:1:1:1 ratio. These 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, gene expression, cell motility, cell division and cell death. This gene encodes the alpha-1E subunit of the R-type calcium channels, which belong to the 'high-voltage activated' group that maybe involved in the modulation of firing patterns of neurons important for information processing. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]

CACNA1E Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 69

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001205293.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-181721870-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1346057.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001205293.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	NM_001205293.3	MANE Select	c.2069_2070delGCinsAT	p.Gly690Asp	missense	N/A	NP_001192222.1	Q15878-1
	CACNA1E	NM_000721.4		c.2069_2070delGCinsAT	p.Gly690Asp	missense	N/A	NP_000712.2	Q15878-3
	CACNA1E	NM_001205294.2		c.2069_2070delGCinsAT	p.Gly690Asp	missense	N/A	NP_001192223.1	Q15878-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	ENST00000367573.7	TSL:1 MANE Select	c.2069_2070delGCinsAT	p.Gly690Asp	missense	N/A	ENSP00000356545.2	Q15878-1
	CACNA1E	ENST00000360108.7	TSL:5	c.2069_2070delGCinsAT	p.Gly690Asp	missense	N/A	ENSP00000353222.3	F8W9Z1
	CACNA1E	ENST00000367570.6	TSL:1	c.2069_2070delGCinsAT	p.Gly690Asp	missense	N/A	ENSP00000356542.1	Q15878-3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-181691006;