rs200382504
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS1
The NM_001128840.3(CACNA1D):c.3821C>T(p.Ser1274Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000331 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001128840.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1D | NM_000720.4 | c.3881C>T | p.Ser1294Phe | missense_variant | Exon 31 of 49 | ENST00000288139.11 | NP_000711.1 | |
CACNA1D | NM_001128840.3 | c.3821C>T | p.Ser1274Phe | missense_variant | Exon 30 of 48 | ENST00000350061.11 | NP_001122312.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1D | ENST00000288139.11 | c.3881C>T | p.Ser1294Phe | missense_variant | Exon 31 of 49 | 1 | NM_000720.4 | ENSP00000288139.3 | ||
CACNA1D | ENST00000350061.11 | c.3821C>T | p.Ser1274Phe | missense_variant | Exon 30 of 48 | 1 | NM_001128840.3 | ENSP00000288133.5 |
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 152214Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000231 AC: 58AN: 251496Hom.: 0 AF XY: 0.000213 AC XY: 29AN XY: 135922
GnomAD4 exome AF: 0.000346 AC: 506AN: 1461536Hom.: 0 Cov.: 30 AF XY: 0.000359 AC XY: 261AN XY: 727090
GnomAD4 genome AF: 0.000184 AC: 28AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13AN XY: 74354
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
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The p.Ser1294Phe variant in the CACNA1D gene has not been previously reported in association with disease. This variant has been identified in 36/129196 European Non-Finnish chromosomes (63/282888 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 228465). The CACNA1D gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Ser1294Phe variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PP2; PP3] -
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not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The p.Ser1294Phe va riant in CACNA1D has been previously reported by our laboratory in one individua l with an alternate genetic etiology to explain the hearing loss. This variant was identified in 16/66738 European chromosomes by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs200382504); however, this fre quency in the general population is not high enough to rule out a pathogenic rol e. Computational prediction tools and conservation analyses suggest that this va riant may not impact the protein, though this information is not predictive enou gh to rule out pathogenicity. In summary, while the clinical significance of the p.Ser1294Phe variant is uncertain, these data suggest that it is more likely to be benign. -
Inborn genetic diseases Uncertain:1
The c.3881C>T (p.S1294F) alteration is located in exon 31 (coding exon 31) of the CACNA1D gene. This alteration results from a C to T substitution at nucleotide position 3881, causing the serine (S) at amino acid position 1294 to be replaced by a phenylalanine (F). The in silico prediction for the p.S1294F alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
CACNA1D-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at