rs147146258

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

Scores

10
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 7.57
Variant links:
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
CACNA1DNM_000720.4 linkuse as main transcriptc.3761A>G p.Asn1254Ser missense_variant 30/49 ENST00000288139.11 NP_000711.1
CACNA1DNM_001128840.3 linkuse as main transcriptc.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
CACNA1DENST00000288139.11 linkuse as main transcriptc.3761A>G p.Asn1254Ser missense_variant 30/491 NM_000720.4 ENSP00000288139 P2Q01668-2
CACNA1DENST00000350061.11 linkuse as main transcriptc.3701A>G p.Asn1234Ser missense_variant 29/481 NM_001128840.3 ENSP00000288133 Q01668-1

Frequencies

GnomAD3 genomes
AF:
0.000427
AC:
65
AN:
152230
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00115
Gnomad SAS
AF:
0.000827
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000647
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000537
AC:
135
AN:
251494
Hom.:
1
AF XY:
0.000544
AC XY:
74
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000694
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.000598
Gnomad SAS exome
AF:
0.000392
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000686
Gnomad OTH exome
AF:
0.000977
GnomAD4 exome
AF:
0.000837
AC:
1221
AN:
1459354
Hom.:
3
Cov.:
30
AF XY:
0.000843
AC XY:
612
AN XY:
726182
show subpopulations
Gnomad4 AFR exome
AF:
0.000479
Gnomad4 AMR exome
AF:
0.000872
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.000756
Gnomad4 SAS exome
AF:
0.000534
Gnomad4 FIN exome
AF:
0.0000562
Gnomad4 NFE exome
AF:
0.000910
Gnomad4 OTH exome
AF:
0.00118
GnomAD4 genome
AF:
0.000433
AC:
66
AN:
152348
Hom.:
0
Cov.:
33
AF XY:
0.000349
AC XY:
26
AN XY:
74504
show subpopulations
Gnomad4 AFR
AF:
0.000192
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.000828
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000647
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000590
Hom.:
0
Bravo
AF:
0.000465
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000511
AC:
62
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.000491
EpiControl
AF:
0.00130

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 submitterclinical testingGeneDxJun 01, 2022See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2023- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024- -
not specified Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingGenetic Services Laboratory, University of ChicagoDec 05, 2022DNA 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 24, 2016The 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 submitterclinical testingAmbry GeneticsSep 19, 2022The 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 providedclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de LilleJan 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.77
.;D;.;.;.;.;.;.;.;.;.
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.95
D;D;D;.;D;D;D;D;D;D;D
M_CAP
Benign
0.051
D
MetaRNN
Benign
0.093
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.74
D
MutationAssessor
Benign
0.71
.;N;.;.;.;N;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-3.5
.;D;.;.;D;D;.;.;D;.;.
REVEL
Uncertain
0.47
Sift
Benign
0.18
.;T;.;.;T;T;.;.;T;.;.
Sift4G
Benign
0.37
.;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
0.035
T
GERP RS
5.9
Varity_R
0.33
gMVP
0.64

Splicing

Name
Calibrated prediction
Score
Prediction
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs147146258; hg19: chr3-53787624; API