rs199930

Positions:

• chr1-181772165-C-G
• chr1-181772165-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000367573.7(CACNA1E):​c.5073C>G​(p.Asn1691Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1691S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNA1E ENST00000367573.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1E. . Gene score misZ 5.8125 (greater than the threshold 3.09). Trascript score misZ 6.7013 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 69.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2511331).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.5073C>G	p.Asn1691Lys	missense_variant	37/48	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.5073C>G	p.Asn1691Lys	missense_variant	37/48	1	NM_001205293.3	ENSP00000356545	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.017
DANN	Benign	0.95
DEOGEN2	Uncertain	0.49	.;.;.;T;T;.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.83	.;.;T;.;T;T;T;T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.13	N;.;.;N;.;N;N;.
MutationTaster	Benign	0.42	P;P;P;P;P;P;P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.68	N;.;N;N;.;.;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.71	T;.;T;T;.;.;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.0020	B;B;.;B;.;B;B;B
Vest4		0.14
MutPred		0.52		Gain of methylation at N1691 (P = 0.0011);.;.;Gain of methylation at N1691 (P = 0.0011);.;Gain of methylation at N1691 (P = 0.0011);Gain of methylation at N1691 (P = 0.0011);.;
MVP		0.67
MPC		1.5
ClinPred		0.13	T
GERP RS		-5.5
Varity_R		0.049
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199930; hg19: chr1-181741301;