rs200796487
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_001843.4(CNTN1):c.3031G>A(p.Gly1011Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000145 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
CNTN1
NM_001843.4 missense
NM_001843.4 missense
Scores
2
16
Clinical Significance
Conservation
PhyloP100: 4.43
Genes affected
CNTN1 (HGNC:2171): (contactin 1) The protein encoded by this gene is a member of the immunoglobulin superfamily. It is a glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein that functions as a cell adhesion molecule. It may play a role in the formation of axon connections in the developing nervous system. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.08469844).
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000592 (9/152044) while in subpopulation SAS AF= 0.000207 (1/4822). AF 95% confidence interval is 0.0000477. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 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 |
---|---|---|---|---|---|---|---|
CNTN1 | NM_001843.4 | c.3031G>A | p.Gly1011Ser | missense_variant | 24/24 | ENST00000551295.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNTN1 | ENST00000551295.7 | c.3031G>A | p.Gly1011Ser | missense_variant | 24/24 | 1 | NM_001843.4 | P3 | |
CNTN1 | ENST00000347616.5 | c.3031G>A | p.Gly1011Ser | missense_variant | 23/23 | 1 | P3 | ||
CNTN1 | ENST00000348761.2 | c.2998G>A | p.Gly1000Ser | missense_variant | 22/22 | 1 | A1 | ||
CNTN1 | ENST00000548481.1 | c.*106G>A | 3_prime_UTR_variant, NMD_transcript_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152044Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251354Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135852
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GnomAD4 exome AF: 0.000154 AC: 225AN: 1461764Hom.: 0 Cov.: 31 AF XY: 0.000139 AC XY: 101AN XY: 727198
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GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152044Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74248
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Compton-North congenital myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CNTN1 protein function. ClinVar contains an entry for this variant (Variation ID: 451957). This variant has not been reported in the literature in individuals affected with CNTN1-related conditions. This variant is present in population databases (rs200796487, gnomAD 0.03%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1011 of the CNTN1 protein (p.Gly1011Ser). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2017 | A variant of uncertain significance has been identified in the CNTN1 gene. The c.3031 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3031 G>A variant is observed in 4/16510 (0.2%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.3031 G>A creates a cryptic acceptor site which may supplant the natural acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If the c.3031 G>A variant does not impact splicing, it will result in a G1011S missense variant. The G1011S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Serine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;.
MutationTaster
Benign
N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;B;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at