rs147146258
Positions:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2
The NM_000720.4(CACNA1D):c.3761A>G(p.Asn1254Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000799 in 1,611,702 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00084 ( 3 hom. )
Consequence
CACNA1D
NM_000720.4 missense
NM_000720.4 missense
Scores
10
9
Clinical Significance
Conservation
PhyloP100: 7.57
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 Benign. Variant got -10 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1D. . Gene score misZ 4.5817 (greater than the threshold 3.09). Trascript score misZ 6.6047 (greater than threshold 3.09). GenCC has associacion of gene with sinoatrial node dysfunction and deafness, aldosterone-producing adenoma with seizures and neurological abnormalities.
BP4
Computational evidence support a benign effect (MetaRNN=0.09306714).
BP6
Variant 3-53753597-A-G is Benign according to our data. Variant chr3-53753597-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504807.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}. Variant chr3-53753597-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000433 (66/152348) while in subpopulation EAS AF= 0.00116 (6/5192). AF 95% confidence interval is 0.000502. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1D | NM_000720.4 | c.3761A>G | p.Asn1254Ser | missense_variant | 30/49 | ENST00000288139.11 | NP_000711.1 | |
CACNA1D | NM_001128840.3 | c.3701A>G | p.Asn1234Ser | missense_variant | 29/48 | ENST00000350061.11 | NP_001122312.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1D | ENST00000288139.11 | c.3761A>G | p.Asn1254Ser | missense_variant | 30/49 | 1 | NM_000720.4 | ENSP00000288139 | P2 | |
CACNA1D | ENST00000350061.11 | c.3701A>G | p.Asn1234Ser | missense_variant | 29/48 | 1 | NM_001128840.3 | ENSP00000288133 |
Frequencies
GnomAD3 genomes AF: 0.000427 AC: 65AN: 152230Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000537 AC: 135AN: 251494Hom.: 1 AF XY: 0.000544 AC XY: 74AN XY: 135922
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GnomAD4 exome AF: 0.000837 AC: 1221AN: 1459354Hom.: 3 Cov.: 30 AF XY: 0.000843 AC XY: 612AN XY: 726182
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GnomAD4 genome AF: 0.000433 AC: 66AN: 152348Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26AN XY: 74504
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 01, 2022 | See Variant Classification Assertion Criteria. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | - - |
not specified Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 05, 2022 | DNA sequence analysis of the CACNA1D gene demonstrated a sequence change, c.3761A>G, in exon 30 that results in an amino acid change, p.Asn1254Ser. This sequence change does not appear to have been previously described in individuals with CACNA1D-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.05% in the overall population (dbSNP rs147146258). The p.Asn1254Ser change affects a highly conserved amino acid residue located in a domain of the CACNA1D protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asn1254Ser substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asn1254Ser change remains unknown at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 24, 2016 | The p.Asn1254Ser variant in CACNA1D has not been previously reported in individu als with hearing loss, but has been identified in several populations by the Exo me Aggregation Consortium including 0.1% (39/66732) of European chromosomes (ExA C, http://exac.broadinstitute.org; dbSNP rs147146258). Although this variant has been seen in the general population, its frequency is not high enough to rule o ut a pathogenic role. Computational prediction tools and conservation analyses d o not provide strong support for or against an impact to the protein. In summary , the clinical significance of the p.Asn1254Ser variant is uncertain. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 19, 2022 | The c.3761A>G (p.N1254S) alteration is located in exon 30 (coding exon 30) of the CACNA1D gene. This alteration results from a A to G substitution at nucleotide position 3761, causing the asparagine (N) at amino acid position 1254 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Intellectual disability Benign:1
Likely benign, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;D;.;.;.;.;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;.;D;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;N;.;.;.;N;.;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;D;.;.;D;D;.;.;D;.;.
REVEL
Uncertain
Sift
Benign
.;T;.;.;T;T;.;.;T;.;.
Sift4G
Benign
.;T;.;.;T;T;.;.;T;.;.
Polyphen
0.13, 0.54, 0.89
.;B;.;P;P;.;.;.;P;.;.
Vest4
0.69, 0.68, 0.68
MVP
0.88
MPC
1.7
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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