chr9-78266441-G-C
Variant summary
Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PVS1_StrongBS1BS2
The NM_001330691.3(CEP78):c.1846-1G>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,578,644 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001330691.3 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Our verdict: Likely_benign. The variant received -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00185 AC: 281AN: 152040Hom.: 1 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00187 AC: 425AN: 226736 AF XY: 0.00205 show subpopulations
GnomAD4 exome AF: 0.00324 AC: 4619AN: 1426486Hom.: 11 Cov.: 29 AF XY: 0.00327 AC XY: 2311AN XY: 705958 show subpopulations
GnomAD4 genome AF: 0.00185 AC: 282AN: 152158Hom.: 1 Cov.: 32 AF XY: 0.00161 AC XY: 120AN XY: 74370 show subpopulations
ClinVar
Submissions by phenotype
not provided Benign:2
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CEP78: PVS1:Moderate, BS2 -
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The c.1849-1G>C variant in CEP78 has not been previously reported in individuals with rod-cone dystrophy, but has been reported by our laboratory in the heterozygous state in 5 individuals with hearing loss, including 2 who had alternate explanations of the hearing loss. This variant has been identified in 0.3% (350/120170) of European chromosomes, including 2 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs146563928). This variant occurs in the last exon of the gene and it is in the invariant region (+/- 1,2) of the splice consensus sequence and is expected to impact the splice site. Computation splice tools suggests the variant creates a cryptic 3' splice site 6 bp downstream of the original splice site which is predicted to result in an in-frame deletion of two amino acids; however these tools may not accurately reflect impact of the variant on splicing. While the clinical significance of the c.1849-1G>C variant is uncertain, the frequency data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1, BP5, PP3. -
Cone-rod dystrophy and hearing loss 1 Uncertain:1
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Retinal dystrophy Uncertain:1
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CEP78-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