rs369194462
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000720.4(CACNA1D):c.6253-11T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,612,796 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00056 ( 9 hom. )
Consequence
CACNA1D
NM_000720.4 splice_polypyrimidine_tract, intron
NM_000720.4 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.0001366
2
Clinical Significance
Conservation
PhyloP100: -0.609
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 -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 3-53811102-T-C is Benign according to our data. Variant chr3-53811102-T-C is described in ClinVar as [Benign]. Clinvar id is 504812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000236 (36/152236) while in subpopulation SAS AF= 0.00705 (34/4822). AF 95% confidence interval is 0.00519. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 9 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1D | NM_000720.4 | c.6253-11T>C | splice_polypyrimidine_tract_variant, intron_variant | ENST00000288139.11 | NP_000711.1 | |||
CACNA1D | NM_001128840.3 | c.6193-11T>C | splice_polypyrimidine_tract_variant, intron_variant | ENST00000350061.11 | NP_001122312.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1D | ENST00000288139.11 | c.6253-11T>C | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000720.4 | ENSP00000288139 | P2 | |||
CACNA1D | ENST00000350061.11 | c.6193-11T>C | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_001128840.3 | ENSP00000288133 |
Frequencies
GnomAD3 genomes AF: 0.000237 AC: 36AN: 152118Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00106 AC: 267AN: 251426Hom.: 2 AF XY: 0.00157 AC XY: 214AN XY: 135900
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GnomAD4 exome AF: 0.000559 AC: 817AN: 1460560Hom.: 9 Cov.: 30 AF XY: 0.000882 AC XY: 641AN XY: 726710
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GnomAD4 genome AF: 0.000236 AC: 36AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29AN XY: 74442
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ClinVar
Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 30, 2019 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 20, 2018 | c.6253-11T>C in Intron 48 of CACNA1D: This variant is not expected to have clini cal significance because it has been identified in 0.9% (265/30782) of South Asi an chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org; dbSNP rs369194462). In addition, splice predictions do not predict an impact to splicing and a T>C change at this position does not diverge from th e splice consensus sequence and is therefore unlikely to impact splicing.ACMG/AM P Criteria applied: BS1, BS2, BP4. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at