4-102869193-C-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001008388.5(CISD2):c.103+6C>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000375 in 1,599,368 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000035 ( 0 hom. )
Consequence
CISD2
NM_001008388.5 splice_donor_region, intron
NM_001008388.5 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0004549
2
Clinical Significance
Conservation
PhyloP100: 1.03
Genes affected
CISD2 (HGNC:24212): (CDGSH iron sulfur domain 2) The protein encoded by this gene is a zinc finger protein that localizes to the endoplasmic reticulum. The encoded protein binds an iron/sulfur cluster and may be involved in calcium homeostasis. Defects in this gene are a cause of Wolfram syndrome 2. [provided by RefSeq, Mar 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.59).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CISD2 | NM_001008388.5 | c.103+6C>A | splice_donor_region_variant, intron_variant | ENST00000273986.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CISD2 | ENST00000273986.10 | c.103+6C>A | splice_donor_region_variant, intron_variant | 1 | NM_001008388.5 | P1 | |||
CISD2 | ENST00000574446.1 | c.103+6C>A | splice_donor_region_variant, intron_variant, NMD_transcript_variant | 5 | |||||
CISD2 | ENST00000646632.1 | c.103+6C>A | splice_donor_region_variant, intron_variant, NMD_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000346 AC: 5AN: 1447170Hom.: 0 Cov.: 33 AF XY: 0.00000557 AC XY: 4AN XY: 718262
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 05, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. This variant has not been reported in the literature in individuals affected with CISD2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the CISD2 gene. It does not directly change the encoded amino acid sequence of the CISD2 protein. It affects a nucleotide within the consensus splice site. - |
Wolfram syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 29, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
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