chr1-181724499-G-C

Position:

• chr1-181724499-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_Moderate PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001205293.3(CACNA1E):​c.2104G>C​(p.Ala702Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A702S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1E NM_001205293.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.73

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 Pathogenic. Variant got 15 ACMG points.

• PS1: Transcript NM_001205293.3 (CACNA1E) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001205293.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-181724499-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 1-181724499-G-C is Pathogenic according to our data. Variant chr1-181724499-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427007.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-181724499-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1E	NM_001205293.3	c.2104G>C	p.Ala702Pro	missense_variant	17/48	ENST00000367573.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1E	ENST00000367573.7	c.2104G>C	p.Ala702Pro	missense_variant	17/48	1	NM_001205293.3	A2
CACNA1E	ENST00000367570.6	c.2104G>C	p.Ala702Pro	missense_variant	17/47	1		P4
CACNA1E	ENST00000621791.4	c.2104G>C	p.Ala702Pro	missense_variant	17/46	1		A2
CACNA1E	ENST00000360108.7	c.2104G>C	p.Ala702Pro	missense_variant	17/47	5		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 20, 2016

The A702P variantl has not been published as pathogenic, nor has it been reported as a benign variant to our knowledge.The A702P variant was not observed in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a semi-conservative amino acid substitution that occurs at a conserved position within the transmembrane segment S6 of the second homologous domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, the A702P variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;D;.;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D;.;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;.;M;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-4.3	D;.;D;D;.;.;.;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D;.;D;D;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;D;.;D
Vest4		0.93
MutPred		0.77		Loss of stability (P = 0.0724);Loss of stability (P = 0.0724);Loss of stability (P = 0.0724);Loss of stability (P = 0.0724);Loss of stability (P = 0.0724);Loss of stability (P = 0.0724);Loss of stability (P = 0.0724);Loss of stability (P = 0.0724);
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.91
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs12131800; hg19: chr1-181693635;