rs370377460
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_005076.5(CNTN2):c.215+6G>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 0.0000719 in 1,612,916 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000078 ( 0 hom. )
Consequence
CNTN2
NM_005076.5 splice_donor_region, intron
NM_005076.5 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00006677
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.7).
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000078 (114/1460660) while in subpopulation NFE AF= 0.000102 (113/1111640). AF 95% confidence interval is 0.0000859. There are 0 homozygotes in gnomad4_exome. There are 52 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNTN2 | NM_005076.5 | c.215+6G>A | 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>A | splice_donor_region_variant, intron_variant | 1 | NM_005076.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152256Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
2
AN:
152256
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000163 AC: 4AN: 245448Hom.: 0 AF XY: 0.00000749 AC XY: 1AN XY: 133424
GnomAD3 exomes
AF:
AC:
4
AN:
245448
Hom.:
AF XY:
AC XY:
1
AN XY:
133424
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000780 AC: 114AN: 1460660Hom.: 0 Cov.: 32 AF XY: 0.0000716 AC XY: 52AN XY: 726626
GnomAD4 exome
AF:
AC:
114
AN:
1460660
Hom.:
Cov.:
32
AF XY:
AC XY:
52
AN XY:
726626
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74392
GnomAD4 genome
?
AF:
AC:
2
AN:
152256
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74392
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Epilepsy, familial adult myoclonic, 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | 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 0.004%). 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: 848625). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
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