rs398122827
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PM4_SupportingPP3PP5_Very_Strong
The NM_000720.4(CACNA1D):c.1208_1209insGGG(p.Gly403dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,284 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
CACNA1D
NM_000720.4 disruptive_inframe_insertion
NM_000720.4 disruptive_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 10.0
Publications
3 publications found
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]
CACNA1D Gene-Disease associations (from GenCC):
- aldosterone-producing adenoma with seizures and neurological abnormalitiesInheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina, G2P
- complex neurodevelopmental disorderInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- sinoatrial node dysfunction and deafnessInheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000720.4. Strenght limited to Supporting due to length of the change: 1aa.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 3-53673802-T-TGGG is Pathogenic according to our data. Variant chr3-53673802-T-TGGG is described in ClinVar as Pathogenic. ClinVar VariationId is 39709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000720.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CACNA1D | NM_000720.4 | MANE Plus Clinical | c.1208_1209insGGG | p.Gly403dup | disruptive_inframe_insertion | Exon 8 of 49 | NP_000711.1 | Q01668-2 | |
| CACNA1D | NM_001128840.3 | MANE Select | c.1220+678_1220+679insGGG | intron | N/A | NP_001122312.1 | Q01668-1 | ||
| CACNA1D | NM_001128839.3 | c.1220+678_1220+679insGGG | intron | N/A | NP_001122311.1 | Q01668-3 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CACNA1D | ENST00000288139.11 | TSL:1 MANE Plus Clinical | c.1208_1209insGGG | p.Gly403dup | disruptive_inframe_insertion | Exon 8 of 49 | ENSP00000288139.3 | Q01668-2 | |
| CACNA1D | ENST00000350061.11 | TSL:1 MANE Select | c.1220+678_1220+679insGGG | intron | N/A | ENSP00000288133.5 | Q01668-1 | ||
| CACNA1D | ENST00000481478.2 | TSL:1 | c.1220+678_1220+679insGGG | intron | N/A | ENSP00000418014.2 | H0Y879 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00000795 AC: 2AN: 251492 AF XY: 0.00000736 show subpopulations
GnomAD2 exomes
AF:
AC:
2
AN:
251492
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460284Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726578 show subpopulations
GnomAD4 exome
AF:
AC:
3
AN:
1460284
Hom.:
Cov.:
30
AF XY:
AC XY:
2
AN XY:
726578
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33442
American (AMR)
AF:
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26130
East Asian (EAS)
AF:
AC:
0
AN:
39694
South Asian (SAS)
AF:
AC:
3
AN:
86216
European-Finnish (FIN)
AF:
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1110560
Other (OTH)
AF:
AC:
0
AN:
60342
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
3
-
-
Sinoatrial node dysfunction and deafness (3)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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