rs756896276
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_003632.3(CNTNAP1):c.1677G>A(p.Trp559Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
CNTNAP1
NM_003632.3 stop_gained
NM_003632.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.06
Genes affected
CNTNAP1 (HGNC:8011): (contactin associated protein 1) The gene product was initially identified as a 190-kD protein associated with the contactin-PTPRZ1 complex. The 1,384-amino acid protein, also designated p190 or CASPR for 'contactin-associated protein,' includes an extracellular domain with several putative protein-protein interaction domains, a putative transmembrane domain, and a 74-amino acid cytoplasmic domain. Northern blot analysis showed that the gene is transcribed predominantly in brain as a transcript of 6.2 kb, with weak expression in several other tissues tested. The architecture of its extracellular domain is similar to that of neurexins, and this protein may be the signaling subunit of contactin, enabling recruitment and activation of intracellular signaling pathways in neurons. [provided by RefSeq, Jan 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-42689569-G-A is Pathogenic according to our data. Variant chr17-42689569-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 590918.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNTNAP1 | NM_003632.3 | c.1677G>A | p.Trp559Ter | stop_gained | 11/24 | ENST00000264638.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNTNAP1 | ENST00000264638.9 | c.1677G>A | p.Trp559Ter | stop_gained | 11/24 | 1 | NM_003632.3 | P1 | |
CNTNAP1 | ENST00000591662.1 | c.1677G>A | p.Trp559Ter | stop_gained, NMD_transcript_variant | 11/24 | 1 | |||
ENST00000592440.1 | n.364-6027C>T | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152036Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251434Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135888
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461686Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 727148
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152036Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74252
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Neuropathy, congenital hypomyelinating, 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 27, 2018 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A
Vest4
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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