Genetic Variant CACNA1E:p.Gly690Val (chr1-181721870-GC-TG) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is The variant received 8 classification points (ACMG Germline Pathogenicity v2019). PS1PM1PM2

The NM_001205293.3(CACNA1E):c.2069_2070delGCinsTG (p.Gly690Val) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.02). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G690D: Uncertain_significance (ClinVar VariationId 521400, 1 star)

Frequency

Genomes: not found (cov: 32)

Consequence

CACNA1E
NM_001205293.3 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.02

Publications

0 publications found

Variant links:

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: Ambry Genetics, G2P, Illumina, Labcorp Genetics (formerly Invitae)
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

CACNA1E links:

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new If you want to explore the variant's impact on the transcript NM_001205293.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 8 points.

Show applied only (3)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, 1-star ClinVar pathogenic — strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 1 star).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 1 benign (OR vs. background: 8.3).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
CACNA1E NM_001205293.3	MANE Select	c.2069_2070delGCinsTG p.Gly690Val	missense	N/A	Prot: NP_001192222.1 UniProt: Q15878-1
CACNA1E NM_000721.4		c.2069_2070delGCinsTG p.Gly690Val	missense	N/A	Prot: NP_000712.2 UniProt: Q15878-3
CACNA1E NM_001205294.2		c.2069_2070delGCinsTG p.Gly690Val	missense	N/A	Prot: NP_001192223.1 UniProt: Q15878-2

CACNA1E NM_001205293.3

MANE Select

HGVSc / HGVSpc.2069_2070delGCinsTGp.Gly690Val

Exon rankN/A

missense

Prot: NP_001192222.1UniProt: Q15878-1

CACNA1E NM_000721.4

HGVSc / HGVSpc.2069_2070delGCinsTGp.Gly690Val

Exon rankN/A

missense

Prot: NP_000712.2UniProt: Q15878-3

CACNA1E NM_001205294.2

HGVSc / HGVSpc.2069_2070delGCinsTGp.Gly690Val

Exon rankN/A

missense

Prot: NP_001192223.1UniProt: Q15878-2

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
CACNA1E ENST00000367573.7	TSL:1MANE Select	c.2069_2070delGCinsTG p.Gly690Val	missense	N/A	Prot: ENSP00000356545.2 UniProt: Q15878-1
CACNA1E ENST00000360108.7	TSL:5	c.2069_2070delGCinsTG p.Gly690Val	missense	N/A	Prot: ENSP00000353222.3 UniProt: F8W9Z1
CACNA1E ENST00000367570.6	TSL:1	c.2069_2070delGCinsTG p.Gly690Val	missense	N/A	Prot: ENSP00000356542.1 UniProt: Q15878-3

CACNA1E ENST00000367573.7

TSL:1MANE Select

HGVSc / HGVSpc.2069_2070delGCinsTGp.Gly690Val

Exon rankN/A

missense

Prot: ENSP00000356545.2UniProt: Q15878-1

CACNA1E ENST00000360108.7

TSL:5

HGVSc / HGVSpc.2069_2070delGCinsTGp.Gly690Val

Exon rankN/A

missense

Prot: ENSP00000353222.3UniProt: F8W9Z1

CACNA1E ENST00000367570.6

TSL:1

HGVSc / HGVSpc.2069_2070delGCinsTGp.Gly690Val

Exon rankN/A

missense

Prot: ENSP00000356542.1UniProt: Q15878-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	8.0

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence