rs1553360130

Positions:

• chr1-181794864-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001205293.3(CACNA1E):​c.6028G>A​(p.Val2010Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000206 in 1,455,966 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNA1E NM_001205293.3 missense, splice_region
• Scores: Splicing: ADA: 0.9776
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.54

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
• BP6: Variant 1-181794864-G-A is Benign according to our data. Variant chr1-181794864-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521249.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.6028G>A	p.Val2010Met	missense_variant, splice_region_variant	Exon 46 of 48	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.6028G>A	p.Val2010Met	missense_variant, splice_region_variant	Exon 46 of 48	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.5971G>A	p.Val1991Met	missense_variant, splice_region_variant	Exon 45 of 47	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.5899G>A	p.Val1967Met	missense_variant, splice_region_variant	Exon 45 of 47	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.5842G>A	p.Val1948Met	missense_variant, splice_region_variant	Exon 44 of 46	1		ENSP00000481619.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455966 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723990

Gnomad4 AFR exome AF: 0.0000603

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	.;.;.;T;T;.;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	.;.;D;.;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.5	.;.;.;L;.;.;L;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.62	N;.;N;N;.;.;.;.
REVEL	Uncertain	0.48
Sift	Benign	0.21	T;.;T;T;.;.;.;.
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T
Polyphen		0.99	D;B;.;.;.;D;.;B
Vest4		0.55
MutPred		0.22		Loss of stability (P = 0.065);.;.;.;.;Loss of stability (P = 0.065);.;.;
MVP		0.85
MPC		0.83
ClinPred		0.63	D
GERP RS		5.9
Varity_R		0.13
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.0		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: rs1553360130; hg19: chr1-181764000;