1-181721870-G-T

Variant names:

• chr1-181721870-G-T
• rs1361083258
• NM_001205293.3:c.2069G>T
• CACNA1E p.Gly690Val

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+10 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 10 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PP3_StrongPP5_Moderate

The NM_001205293.3(CACNA1E):c.2069G>T (p.Gly690Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.02). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★). 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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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: 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 10 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar 1-star pathogenic — moderate (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 1 star(s).

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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CACNA1E NM_001205293.3	MANE Select	c.2069G>T p.Gly690Val	missense	Exon 16 of 48	Prot: NP_001192222.1 UniProt:
	CACNA1E NM_000721.4		c.2069G>T p.Gly690Val	missense	Exon 16 of 47	Prot: NP_000712.2 UniProt:
	CACNA1E NM_001205294.2		c.2069G>T p.Gly690Val	missense	Exon 16 of 46	Prot: NP_001192223.1 UniProt:

CACNA1E NM_001205293.3

MANE Select

HGVSc / HGVSpc.2069G>Tp.Gly690Val

Exon rankExon 16 of 48

missense

Prot: NP_001192222.1UniProt: Q15878-1

CACNA1E NM_000721.4

HGVSc / HGVSpc.2069G>Tp.Gly690Val

Exon rankExon 16 of 47

missense

Prot: NP_000712.2UniProt: Q15878-3

CACNA1E NM_001205294.2

HGVSc / HGVSpc.2069G>Tp.Gly690Val

Exon rankExon 16 of 46

missense

Prot: NP_001192223.1UniProt: Q15878-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CACNA1E ENST00000367573.7	TSL:1MANE Select	c.2069G>T p.Gly690Val	missense	Exon 16 of 48	Prot: ENSP00000356545.2 UniProt:
	CACNA1E ENST00000360108.7	TSL:5	c.2069G>T p.Gly690Val	missense	Exon 16 of 47	Prot: ENSP00000353222.3 UniProt:
	CACNA1E ENST00000367570.6	TSL:1	c.2069G>T p.Gly690Val	missense	Exon 16 of 47	Prot: ENSP00000356542.1 UniProt:

CACNA1E ENST00000367573.7

TSL:1MANE Select

HGVSc / HGVSpc.2069G>Tp.Gly690Val

Exon rankExon 16 of 48

missense

Prot: ENSP00000356545.2UniProt: Q15878-1

CACNA1E ENST00000360108.7

TSL:5

HGVSc / HGVSpc.2069G>Tp.Gly690Val

Exon rankExon 16 of 47

missense

Prot: ENSP00000353222.3UniProt: F8W9Z1

CACNA1E ENST00000367570.6

TSL:1

HGVSc / HGVSpc.2069G>Tp.Gly690Val

Exon rankExon 16 of 47

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:27
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
FuncVEP CTI	Pathogenic	0.98
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	11
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	8/92	disease causing
MutationAssessor	Uncertain	2.2	M
PhyloP100	Pathogenic	8.0
popEVE	Pathogenic	-5.4
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.92
VESM-3B	Benign	-13

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.070
SpliceAI score (max)	Benign	0.10	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

Other links and lift over

dbSNP: rs1361083258;

hg19: chr1-181691006;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar