rs200910800
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BS1_Supporting
The NM_000720.4(CACNA1D):āc.1351G>Cā(p.Glu451Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,614,270 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00018 ( 0 hom., cov: 32)
Exomes š: 0.00028 ( 0 hom. )
Consequence
CACNA1D
NM_000720.4 missense
NM_000720.4 missense
Scores
4
6
3
Clinical Significance
Conservation
PhyloP100: 9.96
Genes affected
CACNA1D (HGNC:1391): (calcium voltage-gated channel subunit alpha1 D) Voltage-dependent calcium 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, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, namely alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1D subunit. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, CACNA1D
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000177 (27/152378) while in subpopulation NFE AF= 0.000368 (25/68024). AF 95% confidence interval is 0.000255. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1D | NM_000720.4 | c.1351G>C | p.Glu451Gln | missense_variant | 9/49 | ENST00000288139.11 | |
CACNA1D | NM_001128840.3 | c.1351G>C | p.Glu451Gln | missense_variant | 9/48 | ENST00000350061.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1D | ENST00000288139.11 | c.1351G>C | p.Glu451Gln | missense_variant | 9/49 | 1 | NM_000720.4 | P2 | |
CACNA1D | ENST00000350061.11 | c.1351G>C | p.Glu451Gln | missense_variant | 9/48 | 1 | NM_001128840.3 |
Frequencies
GnomAD3 genomes ? AF: 0.000177 AC: 27AN: 152260Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000151 AC: 38AN: 251450Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135912
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GnomAD4 exome AF: 0.000276 AC: 403AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.000253 AC XY: 184AN XY: 727246
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GnomAD4 genome ? AF: 0.000177 AC: 27AN: 152378Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74520
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 06, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CACNA1D p.Glu451Gln variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs200910800), LOVD 3.0 and ClinVar (classified as a VUS by Laboratory for Molecular Medicine). The variant was identified in control databases in 42 of 282848 chromosomes at a frequency of 0.000148 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 39 of 129154 chromosomes (freq: 0.000302), Other in 1 of 7222 chromosomes (freq: 0.000139) and African in 2 of 24972 chromosomes (freq: 0.00008), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish) or South Asian populations. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The p.Glu451 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 451 of the CACNA1D protein (p.Glu451Gln). This variant is present in population databases (rs200910800, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CACNA1D-related conditions. ClinVar contains an entry for this variant (Variation ID: 228464). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1D protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 24, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 16, 2015 | The p.Glu451Gln variant in CACNA1D has not been previously reported in individua ls with hearing loss, but has been identified in 12/66694 European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200910800). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational predi ction tools and conservation analysis do not provide strong support for or again st an impact to the protein. In summary, the clinical significance of the p.Glu4 51Gln variant is uncertain. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 15, 2021 | The c.1351G>C (p.E451Q) alteration is located in exon 9 (coding exon 9) of the CACNA1D gene. This alteration results from a G to C substitution at nucleotide position 1351, causing the glutamic acid (E) at amino acid position 451 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
Polyphen
0.60, 0.99, 0.95
.;P;.;D;D;.;.;.;P
Vest4
0.45, 0.52, 0.48
MVP
0.92
MPC
1.7
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at