chr1-205058071-G-C
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_005076.5(CNTN2):c.215+6G>C 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 0.000139 in 1,612,916 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00013 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )
Consequence
CNTN2
NM_005076.5 splice_donor_region, intron
NM_005076.5 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00008703
2
Clinical Significance
Conservation
PhyloP100: -0.262
Genes affected
CNTN2 (HGNC:2172): (contactin 2) This gene encodes a member of the contactin family of proteins, part of the immunoglobulin superfamily of cell adhesion molecules. The encoded glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein plays a role in the proliferation, migration, and axon guidance of neurons of the developing cerebellum. A mutation in this gene may be associated with adult myoclonic epilepsy. [provided by RefSeq, Sep 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.7).
BP6
Variant 1-205058071-G-C is Benign according to our data. Variant chr1-205058071-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541410.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000131 (20/152256) while in subpopulation NFE AF= 0.000191 (13/68040). AF 95% confidence interval is 0.000112. There are 1 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNTN2 | NM_005076.5 | c.215+6G>C | splice_donor_region_variant, intron_variant | ENST00000331830.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNTN2 | ENST00000331830.7 | c.215+6G>C | splice_donor_region_variant, intron_variant | 1 | NM_005076.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152256Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.0000570 AC: 14AN: 245448Hom.: 0 AF XY: 0.0000675 AC XY: 9AN XY: 133424
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GnomAD4 exome AF: 0.000140 AC: 204AN: 1460660Hom.: 0 Cov.: 32 AF XY: 0.000145 AC XY: 105AN XY: 726626
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GnomAD4 genome AF: 0.000131 AC: 20AN: 152256Hom.: 1 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74392
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Epilepsy, familial adult myoclonic, 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | This sequence change falls in intron 3 of the CNTN2 gene. It does not directly change the encoded amino acid sequence of the CNTN2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs370377460, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CNTN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 541410). 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. 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. - |
CNTN2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 08, 2019 | 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
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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